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Background: Optimizing linear growth in children during complementary feeding period (CFP) (6-24 months) is critical for their development. Several interventions, such as micronutrient and food supplements, deworming, maternal education, and water, sanitation and hygiene (WASH), could potentially be provided to prevent stunting, but their comparative effectiveness are currently unclear. In this study, we evaluated comparative effectiveness of interventions under these domains on child linear growth outcomes of height-for-age z-score (HAZ) and stunting (HAZ <-2SD) Methods: For this study, we searched for low- and middle-income country (LMIC)-based randomized clinical trials (RCTs) of aforementioned interventions provided to children during CFP. We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We performed random-effects network meta-analysis (NMA) for HAZ and stunting. Results: The evidence base for our NMA was based on 79 RCTs (96 papers) involving 81,786 children. Among the micronutrients, compared to standard-of-care, iron + folic acid (IFA) (mean difference =0.08; 95% credible interval [CrI]: 0.01, 0.15) and multiple micronutrients (MMN) (mean difference =0.06; 95%CrI: 0.01, 0.11) showed improvements for HAZ; MMN also reduced the risks for stunting (RR=0.86; 95%Crl: 0.73, 0.98), whereas IFA did not (RR=0.92; 95%Crl: 0.64, 1.23). For food supplements, flour in the caloric range of 270-340 kcal (RR=0.73; 95%Crl: 0.51, 1.00) and fortified lipid-based nutrient supplements (LNS) containing 220-285 kcal (RR=0.80; 95%Crl: 0.66, 0.97) decreased the risk of stunting compared to standard-of-care, but these interventions and other food supplements did not show improvements for HAZ. Deworming, maternal education, and WASH interventions did not show improvements for HAZ nor stunting. Conclusion: While we found micronutrient and food supplements to be effective for HAZ and/or stunting, the evidence base for other domains in this life stage was limited, highlighting the need for more investigation. Registration: PROSPERO CRD42018110449; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Background: Exclusive breastfeeding (EBF) during the first six months of life is critical for child's linear growth. While there is strong evidence in favor of EBF, the evidence with regards to other interventions for linear growth is unclear. We evaluated intervention domains of micronutrients, food supplements, deworming, maternal education, water sanitation and hygiene (WASH), and kangaroo care, for their comparative effectiveness on linear growth. Methods: For this review, we searched for randomized clinical trials (RCTs) of the interventions provided to infants aged 0-6 months and/or their breastfeeding mothers in low- and middle-income countries reporting on length-for-age z-score (LAZ), stunting, length, and head circumference. We searched for reports published until September 17 th , 2019 and hand-searched bibliographies of existing reviews. For LAZ and stunting, we used network meta-analysis (NMA) to compare the effects of all interventions except for kangaroo care, where we used pairwise meta-analysis to compare its effects versus standard-of-care. For length and head circumference, we qualitatively summarized our findings. Results: We found 29 RCTs (40 papers) involving 35,119 mother and infant pairs reporting on the effects of aforementioned interventions on linear growth outcomes. Our NMA on LAZ found that compared to standard-of-care, multiple micronutrients administered to infants (MMN-C) improved LAZ (mean difference: 0.20; 95% credible interval [CrI]: 0.03,0.35), whereas supplementing breastfeeding mothers with MMN did not (MMN-M, mean difference: -0.02, 95%CrI: -0.18,0.13). No interventions including MMN-C (relative risk: 0.74; 95%CrI: 0.36,1.44) reduced risk for stunting compared to standard-of-care. Kangaroo care, on the other hand, improved head circumference (mean difference: 0.20 cm/week; 95% confidence intervals [CI]: 0.09,0.31 cm/week) and length (mean difference: 0.23 cm/week; 95%CI: 0.10,0.35 cm/week) compared to standard-of-care.   Conclusion: Our study found important improvements for kangaroo care, but we did not find sufficient evidence for other interventions. Registration: PROSPERO CRD42018110450; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Background: Improving the health of pregnant women is important to prevent adverse birth outcomes, such as preterm birth and low birthweight. We evaluated the comparative effectiveness of interventions under the domains of micronutrient, balanced energy protein, deworming, maternal education, and water sanitation and hygiene (WASH) for their effects on these adverse birth outcomes. Methods: For this network meta-analysis, we searched for randomized clinical trials (RCTs) of interventions provided to pregnant women in low- and middle-income countries (LMICs). We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We extracted data from eligible studies for study characteristics, interventions, participants' characteristics at baseline, and birth outcomes. We compared effects on preterm birth (<37 gestational week), low birthweight (LBW; <2500 g), and birthweight (continuous) using studies conducted in LMICs. Results: Our network meta-analyses were based on 101 RCTs (132 papers) pertaining to 206,531 participants. Several micronutrients and balanced energy food supplement interventions demonstrated effectiveness over standard-of-care. For instance, versus standard-of-care, micronutrient supplements for pregnant women, such as iron and calcium, decreased risks of preterm birth (iron: RR=0.70, 95% credible interval [Crl] 0.47, 1.01; calcium: RR=0.76, 95%Crl 0.56, 0.99). Daily intake of 1500kcal of local food decreased the risks of preterm birth (RR=0.36, 95%Crl 0.16, 0.77) and LBW (RR=0.17, 95%Crl 0.09, 0.29), respectively when compared to standard-of-care. Educational and deworming interventions did not show improvements in birth outcomes, and no WASH intervention trials reported on these adverse birth outcomes. Conclusion: We found several pregnancy interventions that improve birth outcomes. However, most clinical trials have only evaluated interventions under a single domain (e.g. micronutrients) even though the causes of adverse birth outcomes are multi-faceted. There is a need to combine interventions that of different domains as packages and test for their effectiveness. Registration: PROSPERO CRD42018110446; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Park JJH et al.)

Objectives: The objective of the study was to outline key considerations for general clinical readers when critically evaluating publications on platform trials and for researchers when designing these types of clinical trials., Study Design and Setting: In this review, we describe key concepts of platform trials with case study discussion of two hallmark platform trials in STAMPEDE and I-SPY2. We provide reader's guide to platform trials with a critical appraisal checklist., Results: Platform trials offer flexibilities of dropping ineffective arms early based on interim data and introducing new arms into the trial. For platform trials, it is important to consider how interventions are compared and evaluated throughout and how new interventions are introduced. For intervention comparisons, it is important to consider what the primary analysis is, what and how many interventions are active simultaneously, and allocation between different arms. Interim evaluation considerations should include the number and timing of interim evaluations and outcomes and statistical rules used to drop interventions. New interventions are usually introduced based on scientific merits, so consideration of these merits is important, together with the timing and mechanisms in which new interventions are added., Conclusion: More efforts are needed to improve the scientific literacy of platform trials. Our review provides an overview of the important concepts of platform trials., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rwanda has identified several targeted HIV prevention strategies, such as promotion of condom use and provision of antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) for female sex workers (FSWs). Given this country's limited resources, understanding how the HIV epidemic will be affected by these strategies is crucial., Methods: We developed a Markov model to estimate the effects of targeted strategies to FSWs on the HIV prevalence/incidence in Rwanda from 2017 to 2027. Our model consists of the six states: HIV-; HIV+ undiagnosed/diagnosed pre-ART; HIV+ diagnosed with/without ART; and death. We considered three populations: FSWs, sex clients and the general population. For the period 2017-2027, the HIV epidemic among each of these population was estimated using Rwanda's demographic, sexual risk behaviour and HIV-associated morbidity and mortality data., Results: Between 2017 and 2027, with no changes in the current condom and ART use, the overall number of people living with HIV is expected to increase from 344,971 to 402,451. HIV incidence will also decrease from 1.36 to 1.20 100 person-years. By 2027, a 30% improvement in consistent condom use among FSWs will result in absolute reduction of HIV prevalence among FSWs, sex clients and the general population by 7.86%, 5.97% and 0.17%, respectively. While recurring HIV testing and improving the ART coverage mildly reduced the prevalence/incidence among FSWs and sex clients, worsening the two (shown by our worst-case scenario) will result in an increase in the HIV prevalence/incidence among FSWs and sex clients. Introduction of PrEP to FSWs in 2019 will reduce the HIV incidence among FSWs by 1.28%., Conclusions: Continued efforts toward improving condom and ART use will be critical for Rwanda to continue their HIV epidemic control. Implementing a targeted intervention strategy in PrEP for FSWs will reduce the HIV epidemic in this high-risk population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Response adaptive randomized clinical trials have gained popularity due to their flexibility for adjusting design components, including arm allocation probabilities, at any point in the trial according to the intermediate results. In the Bayesian framework, allocation probabilities to different treatment arms are commonly defined as functionals of the posterior distributions of parameters of the outcome distribution for each treatment. In a non-conjugate model, however, repeated updates of the posterior distribution can be computationally intensive. In this article, we propose an adaptation of sequential Monte Carlo for efficiently updating the posterior distribution of parameters as new outcomes are observed in a general adaptive trial design. An efficient computational tool facilitates implementation of more flexible designs with more frequent interim looks that can in turn reduce the required sample size and expected number of failures in clinical trials. Moreover, more complex statistical models that reflect realistic modeling assumptions can be used for analysis of trial results., (© The Author 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With advancements in biomarkers and momentum in precision medicine, biomarker-guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine-to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials., (© 2020 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: Concordance between Common Drug Review (CDR) recommendations and provincial plans has been studied previously. However, no study has, to the best of the authors' knowledge, examined the characteristics of CDR recommendations that may be associated with concordance., Methods: Recommendation-decision pairs were collected from the CDR and the provincial plans of Ontario, British Columbia and Alberta. Concordance was evaluated by province. Characteristics of each CDR recommendation were collected, and associations with concordance were evaluated by logistic regression., Results: Recommendation-listing concordance was high. Positive references to cost and clinical outcomes compared to placebo were statistically associated with concordance. Negative references to cost and to the consistency and certainty of economic evidence were statistically associated with discordance. However, these findings were inconsistent across the jurisdictions studied., Conclusion: Although concordance was high, the ability of recommendation characteristics to explain the relationship between province and CDR listing decisions was limited. This exploratory study highlights the complexity of the reimbursement process and possible reasons for drug listing differences across jurisdictions., (Copyright © 2020 Longwoods Publishing.)

Background: Exclusive breastfeeding (EBF) during the first six months of life is critical for child's linear growth. While there is strong evidence in favor of EBF, the evidence with regards to other interventions for linear growth is unclear. We evaluated intervention domains of micronutrients, food supplements, deworming, maternal education, water sanitation and hygiene (WASH), and kangaroo care, for their comparative effectiveness on linear growth. Methods: For this review, we searched for randomized clinical trials (RCTs) of the interventions provided to infants aged 0-6 months and/or their breastfeeding mothers in low- and middle-income countries reporting on length-for-age z-score (LAZ), stunting, length, and head circumference. We searched for reports published until September 17 th , 2019 and hand-searched bibliographies of existing reviews. For LAZ and stunting, we used network meta-analysis (NMA) to compare the effects of all interventions except for kangaroo care, where we used pairwise meta-analysis to compare its effects versus standard-of-care. For length and head circumference, we qualitatively summarized our findings. Results: We found 29 RCTs (40 papers) involving 35,119 mother and infant pairs reporting on the effects of aforementioned interventions on linear growth outcomes. Our NMA on LAZ found that compared to standard-of-care, multiple micronutrients administered to infants (MMN-C) improved LAZ (mean difference: 0.20; 95% credible interval [CrI]: 0.03,0.35), whereas supplementing breastfeeding mothers with MMN did not (MMN-M, mean difference: -0.02, 95%CrI: -0.18,0.13). No interventions including MMN-C (relative risk: 0.74; 95%CrI: 0.36,1.44) reduced risk for stunting compared to standard-of-care. Kangaroo care, on the other hand, improved head circumference (mean difference: 0.20 cm/week; 95% confidence intervals [CI]: 0.09,0.31 cm/week) and length (mean difference: 0.23 cm/week; 95%CI: 0.10,0.35 cm/week) compared to standard-of-care.   Conclusion: Our study found important improvements for kangaroo care, but we did not find sufficient evidence for other interventions. Registration: PROSPERO CRD42018110450; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Park JJH et al.)

Background: Optimizing linear growth in children during complementary feeding period (CFP) (6-24 months) are critical for their development. Several interventions, such as micronutrient and food supplements, deworming, maternal education, and water, sanitation and hygiene (WASH), could potentially be provided to prevent stunting, but their comparative effectiveness is currently unclear. In this study, we evaluated comparative effectiveness of interventions under these domains on child linear growth outcomes of height-for-age z-score (HAZ) and stunting (HAZ <-2SD) Methods: For this study, we searched for low- and middle-income country (LMIC)-based randomized clinical trials (RCTs) of aforementioned interventions provided to children during CFP. We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We performed random-effects network meta-analysis (NMA) for HAZ and stunting. Results: The evidence base for our NMA was based on 79 RCTs (96 papers) involving 81,786 children. Among the micronutrients, compared to standard-of-care, iron + folic acid (IFA) (mean difference =0.08; 95% credible interval [CrI]: 0.01, 0.15) and multiple micronutrients (MMN) (mean difference =0.06; 95%CrI: 0.01, 0.11) showed improvements for HAZ; MMN also reduced the risks for stunting (RR=0.86; 95%Crl: 0.73, 0.98), whereas IFA did not (RR=0.92; 95%Crl: 0.64, 1.23). For food supplements, flour in the caloric range of 270-340 kcal (RR=0.73; 95%Crl: 0.51, 1.00) and fortified lipid-based nutrient supplements (LNS) containing 220-285 kcal (RR=0.80; 95%Crl: 0.66, 0.97) decreased the risk of stunting compared to standard-of-care, but these interventions and other food supplements did not show improvements for HAZ. Deworming, maternal education, and WASH interventions did not show improvements for HAZ nor stunting. Conclusion: While we found micronutrient and food supplements to be effective for HAZ and/or stunting, the evidence base for other domains in this life stage was limited, highlighting the need for more investigation. Registration: PROSPERO CRD42018110449; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Park JJH et al.)

Background: Improving the health of pregnant women is important to prevent adverse birth outcomes, such as preterm birth and low birthweight. We evaluated the comparative effectiveness of interventions under the domains of micronutrient, balanced energy protein, deworming, maternal education, and water sanitation and hygiene (WASH) for their effects on these adverse birth outcomes. Methods: For this network meta-analysis, we searched for randomized clinical trials (RCTs) of interventions provided to pregnant women in low- and middle-income countries (LMICs). We searched for reports published until September 17, 2019 and hand-searched bibliographies of existing reviews. We extracted data from eligible studies for study characteristics, interventions, participants' characteristics at baseline, and birth outcomes. We compared effects on preterm birth (<37 gestational week), low birthweight (LBW; <2500 g), and birthweight (continuous) using studies conducted in LMICs. Results: Our network meta-analyses were based on 101 RCTs (132 papers) pertaining to 206,531 participants. Several micronutrients and balanced energy food supplement interventions demonstrated effectiveness over standard-of-care. For instance, versus standard-of-care, micronutrient supplements for pregnant women, such as iron and calcium, decreased risks of preterm birth (iron: RR=0.70, 95% credible interval [Crl] 0.47, 1.01; calcium: RR=0.76, 95%Crl 0.56, 0.99). Daily intake of 1500kcal of local food decreased the risks of preterm birth (RR=0.36, 95%Crl 0.16, 0.77) and LBW (RR=0.17, 95%Crl 0.09, 0.29), respectively when compared to standard-of-care. Educational and deworming interventions did not show improvements in birth outcomes, and no WASH intervention trials reported on these adverse birth outcomes. Conclusion: We found several pregnancy interventions that improve birth outcomes. However, most clinical trials have only evaluated interventions under a single domain (e.g. micronutrients) even though the causes of adverse birth outcomes are multi-faceted. There is a need to combine interventions that of different domains as packages and test for their effectiveness. Registration: PROSPERO CRD42018110446; registered on 17 October 2018., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Park JJH et al.)

Background: Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used., Methods: We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries., Results: We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500-90 = 410), and the median study duration was 22.3 (IQR: 74.1-42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565-252 = 313), and the median study duration was 60.9 (IQR: 81.3-46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6-4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835-255 = 1580), and the median study duration was 58.9 (IQR: 101.3-36.9 = 64.4) months., Conclusions: We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.

Background: Enrollment of participants to control arms in clinical trials can be challenging. This is particularly an issue in oncology trials where the standard-of-care is shifting rapidly and several promising experimental treatments are undergoing phase III testing. Novel methods for utilizing external control data may mitigate these challenges, but applied examples are sparse. Here, we therefore illustrate how Bayesian dynamic borrowing of external individual patient level control data from similar clinical trials can often reduce randomization to the control intervention without substantially trading-off precision. We further explore which types of scenarios yield viable trade-offs, and which do not., Patients and Methods: We obtained individual patient data on patients being treated with second-line therapy for non-small cell lung cancer from Project Data Sphere with minimal in/exclusion criteria restrictions, and applied Bayesian hierarchical models with uninformative priors to generate illustrative synthetic control groups., Results: Four phase III clinical trials were identified and utilized in our analysis. Even when studies which are knowingly incongruent with one another are selected to generate a synthetic control, the nature of this methodology minimizes improper borrowing from historical data. The use of a small concurrent control group within a trial greatly reduces penalized selection, and our results demonstrate the ability to reduce allocation to the control group by up to 80% with a minimal increase in uncertainty when closely matched historical data is available., Conclusion: Dynamic borrowing using Bayesian hierarchical models with uninformative priors represents a novel approach to utilizing external controls for comparative estimates using single arm evidence.

Background: In September 2018 the FDA provided a draft guidance on master protocols reflecting an increased interest in these designs by industry. Master protocols refer to a single overarching protocol developed to evaluate multiple hypotheses and may be further categorized as basket, umbrella, and platform trials. However, inconsistencies in reporting persist in the literature. We conducted a systematic review to describe master protocol reporting with the goal of facilitating the further development and spread of these innovative trial designs., Methods: We searched MEDLINE, EMBASE, and CENTRAL from inception to April 25, 2019 for English articles on master protocols. This was supplemented by hand searches of trial registries and of the bibliographies of published reviews. We used the FDA's definitions of master protocols as references and compared them to self-reported master protocols., Results: We identified 278 master protocol publications, consisting of 228 protocols and 50 reviews. Sixty-six records provided unique definitions of master protocol types. We observed considerable heterogeneity in definitions of master protocols, and over half (54%) used oncology-specific language. The majority of self-classified master protocols (57%) were consistent with the FDA's definitions of master protocols., Conclusion: The terms 'master protocol', 'basket trial', 'umbrella trial', and 'platform trial' are inconsistently described. Careful treatment of these terms and adherence to the definitions set forth by the FDA will facilitate better understanding of these trial designs and allow them to be used broadly and to their full potential in clinical research. We encourage trial methodologists to use these trial designations when applicable.

Importance: The first 1000 days of life represent a critical window for child development. Pregnancy, exclusive breastfeeding (EBF) period (0-6 months), and complementary feeding (CF) period (6-24 months) have different growth requirements, so separate considerations for intervention strategies are needed. No synthesis to date has attempted to quantify the associations of interventions under multiple domains of micronutrient and balanced energy protein and food supplements, deworming, maternal education, water sanitation, and hygiene across these 3 life periods with birth and growth outcomes., Objective: To determine the magnitude of association of interventions with birth and growth outcomes based on randomized clinical trials (RCTs) conducted in low-income and middle-income countries (LMICs) using Bayesian network meta-analyses., Data Sources: MEDLINE, Embase, and Cochrane databases were searched from their inception up to August 14, 2018., Study Selection: Included were LMIC-based RCTs of interventions provided to pregnant women, infants (0-6 months), and children (6-24 months)., Data Extraction and Synthesis: Two independent reviewers used a standardized data extraction and quality assessment form. Random-effects network meta-analyses were performed for each life period. Effect sizes are reported as odds ratios (ORs) and mean differences (MeanDiffs) for dichotomous and continuous outcomes, with 95% credible intervals (CrIs). This study calculated probabilities of interventions being superior to standard of care by at least a minimal clinically important difference., Main Outcomes and Measures: The study compared ORs on preterm birth and MeanDiffs on birth weight for pregnancy, length for age (LAZ) for EBF, and height for age (HAZ) for CF., Results: Among 302 061 participants in 169 randomized clinical trials, the network meta-analyses found several nutritional interventions that demonstrated greater association with improved birth and growth outcomes compared with standard of care. For instance, compared with standard of care, maternal supplements of multiple micronutrients showed reduced odds for preterm birth (OR, 0.54; 95% CrI, 0.27-0.97) and improved mean birth weight (MeanDiff, 0.08 kg; 95% CrI, 0.00-0.17 kg) but not LAZ during EBF (MeanDiff, -0.02; 95% CrI, -0.18 to 0.14). Supplementing infants and children with multiple micronutrients showed improved LAZ (MeanDiff, 0.20; 95% CrI, 0.03-0.35) and HAZ (MeanDiff, 0.14; 95% CrI, 0.02-0.25). The study found that pregnancy interventions generally had higher probabilities of a minimal clinically importance difference than the interventions for the EBF or CF in the first 1000 days of life., Conclusions and Relevance: These analyses highlight the importance of intervening early for child development, during pregnancy if possible. Results of this study suggest that there is a need to combine interventions from multiple domains and test for their effectiveness as a package.

Recent advancements in genomics have attracted attention towards biomarker-guided trials. These trials aim to identify therapies that target diseases based on their genetic profile, and are especially common in cancer research. Careful incorporation of biomarkers in phase II studies is critical to the selection of candidates for further phase III investigation. This short communication focuses on problems of biomarker test accuracy in biomarker-guided trials. We assessed how diagnostic accuracy of biomarker tests affects type I error rate, statistical power, and sample size requirements of single-arm biomarker-guided trials. In particular, we report how false positive rates (FPRs) of biomarker tests reduce statistical power and type I error for Simon's two-stage design, and the degree of sample size correction required to achieve pre-specified power and type I error with varying FPRs. This was done using a case study based on a previous biomarker-guided single-arm trial that was designed with an assumed tumor response rate of 10% under the null hypothesis and 40% for the alternative hypothesis for the mutant group for 5% type I error and 90% power. With varying FPRs of biomarker tests, we considered two scenarios in which the response rate for the wild-type group was assumed to be lower than the response rate for the mutant group at 5% and 10%. We also developed a simple open-source online trial planner for future investigators to use for their biomarker-guided phase II trials (https://mtek.shinyapps.io/Biomarker&#95;Trial&#95;Planner/).

Background: Typhoid fevers are infections caused by the bacteria Salmonella enterica serovar Typhi (Salmonella Typhi) and Paratyphi A, B and C (Salmonella Paratyphi). Approximately 17.8 million incident cases of typhoid fever occur annually, and incidence is highest in children. The accuracy of current diagnostic tests of typhoid fever is poorly understood. We aimed to determine the comparative accuracy of available tests for the pediatric population., Methods: We first conducted a systematic literature review to identify studies that compared diagnostic tests for typhoid fever in children (aged ≤15 years) to blood culture results. We applied a Bayesian latent-class extension to a network meta-analysis model. We modelled known diagnostic properties of bone marrow culture and the relationship between bone marrow and blood culture as informative priors in a Bayesian framework. We tested sensitivities for the proportion of negative blood samples that were false as well as bone marrow sensitivity and specificity., Results: We found 510 comparisons from 196 studies and 57 specific to the pediatric population. IgM-based tests outperformed their IgG-based counterparts for ELISA and Typhidot tests. The lateral flow IgG test performed comparatively well with 92% sensitivity (72% to 98% across scenario analyses) and 94% specificity. The most sensitive test of those investigated for the South Asian pediatric population was the Reverse Passive Hemagglutination Assay with 99% sensitivity (98% - 100% across scenario analyses). Adding a Widal slide test to other typhoid diagnostics did not substantially improve diagnostic performance beyond the single test alone, however, a lateral flow-based IgG rapid test combined with the typhoid/paratyphoid (TPT) assay yielded improvements in sensitivity without substantial declines in specificity and was the best performing combination test in this setting., Conclusion: In the pediatric population, lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests had high diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. South Asia has the most informed set of data on typhoid diagnostic testing accuracy, and the evidence base in other important regions needs to be expanded., Competing Interests: The authors have declared that no competing interests exist.

Background: Adaptive designs and platform designs are among two common clinical trial innovations that are increasingly being used to manage medical intervention portfolios and attain faster regulatory approvals. Planning of adaptive and platform trials necessitate simulations to understand how a set of adaptation rules will likely affect the properties of the trial. Clinical trial simulations, however, remain a black box to many clinical trials researchers who are not statisticians. Results: In this article we introduce a simple intuitive open-source browser-based clinical trial simulator for planning adaptive and platform trials. The software application is implemented in RShiny and features a graphical user interface that allows the user to set key clinical trial parameters and explore multiple scenarios such as varying treatment effects, control response and adherence, as well as number of interim looks and adaptation rules. The software provides simulation options for a number of designs such as dropping treatment arms for futility, adding a new treatment arm (i.e., platform design), and stopping a trial early based on superiority. All available adaptations are based on underlying Bayesian probabilities. The software comes with a number of graphical outputs to examine properties of individual simulated trials. The main output is a comparison of trial design performance across several simulations, graphically summarizing type I error (false positive risk), power, and expected cost/time to completion of the considered designs. Conclusion: We have developed and validated an intuitive highly efficient clinical trial simulator for planning of clinical trials. The software is open-source and caters to clinical trial investigators who do not have the statistical capacity for trial simulations available in their team. The software can be accessed via any web browser via the following link: https://mtek.shinyapps.io/hect/ ., Competing Interests: No competing interests were disclosed.

Background: Treatment of schizophrenia with first- and second-generation antipsychotics has been associated with elevated prolactin levels, which may increase the risk for prolactin-related adverse events., Methods: Randomized controlled trials (RCTs) included in a recent systematic review were considered for this analysis. A Bayesian network meta-analysis was used to compare changes in prolactin levels in pediatric patients diagnosed with schizophrenia or schizophrenia spectrum disorders treated with second-generation antipsychotics (SGAs)., Results: Five RCTs, including 989 patients combined, have evaluated the changes in prolactin for pediatric patients after 6 weeks of treatment with risperidone, quetiapine, aripiprazole, olanzapine, and paliperidone. In the overall study population, treatment with risperidone was associated with the highest increase in mean prolactin levels compared to other SGAs. Patients treated with risperidone 4-6 mg/day were found to experience the greatest increases (55.06 ng/ml [95% CrI: 40.53-69.58]) in prolactin levels, followed by risperidone 1-3 mg/day, paliperidone 3-6 mg/day, and paliperidone 6-12 mg/day., Conclusions: This study shows that there are differences in SGAs ability to cause hyperprolactinemia. Further, there is clear evidence of safety concerns with risperidone and paliperidone treatment in adolescent schizophrenia patients., Registration: PROSPERO CRD42014009506.

Adaptive clinical trials are an innovative trial design aimed at reducing resources, decreasing time to completion and number of patients exposed to inferior interventions, and improving the likelihood of detecting treatment effects. The last decade has seen an increasing use of adaptive designs, particularly in drug development. They frequently differ importantly from conventional clinical trials as they allow modifications to key trial design components during the trial, as data is being collected, using preplanned decision rules. Adaptive designs have increased likelihood of complexity and also potential bias, so it is important to understand the common types of adaptive designs. Many clinicians and investigators may be unfamiliar with the design considerations for adaptive designs. Given their complexities, adaptive trials require an understanding of design features and sources of bias. Herein, we introduce some common adaptive design elements and biases and specifically address response adaptive randomization, sample size reassessment, Bayesian methods for adaptive trials, seamless trials, and adaptive enrichment using real examples., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Randomized clinical trials (RCT) increasingly investigate combination therapies. Strong biological rationale or early clinical evidence commonly suggest that the effect of the combination treatment is importantly greater than the maximum effect of any of the individual treatments. While these relationships are commonly well-accepted, RCTs do not incorporate them into the design or analysis plans. We therefore propose a simple Bayesian framework for incorporating the known relationships that the effectiveness of a combination treatment exceeds that of any individual treatment, but does not necessarily exceed the sum of individual effects. We term the collation of these two relationships 'fractional additivity'. We performed a binary outcome simulation study of a response adaptive randomized three-arm clinical trial with treatment arms A, B, and A&B that allowed for dropping an inferior treatment arm and terminating the trial early for superiority during any of 4 interim analyses. We compared the Bayesian fractional additivity model to a conventional analysis by measuring the expected proportion of failures, sample size at trial termination, time to termination, and root mean squared error of final estimates. We also compared the fractional additivity model to a 'full additivity' model where the effect of A&B was assumed to be the sum of the effect of A and B. In simulation scenarios where important fractional additivity or full additivity existed, the Bayesian fractional additivity model yielded a 3-4% relative reduction in expected number of failures, and a 30%-50% relative reduction in sample size at trial termination compared to a conventional analysis. These results held true even when the Bayesian fractional additivity model employed a biased prior. The full additivity model had slightly higher gains, but too frequently terminated the trial at the first interim look. In scenarios where no or weak fractional additivity exists, the expected sample size and time to termination were similar for the Bayesian fractional additivity model with a moderately optimistic bias about fractional additivity and the conventional model. Lastly, the fractional additivity model generally yielded similar or lower root mean squared error compared to the other models. In conclusion, our proposed Bayesian fractional additivity model provides an efficient approach for estimating effects of combination treatments in clinical trials. The approach is not only highly applicable in adaptive clinical trials, but also provides added power in a conventional RCT.

Introduction Migraine headache is a neurological disorder whose attacks are associated with nausea, vomiting, photophobia and phonophobia. Treatments for migraine aim to either prevent attacks before they have started or relieve attacks (abort) after onset of symptoms and range from complementary therapies to pharmacological interventions. A number of treatment-related adverse events such as somnolence, fatigue, and chest discomfort have previously been reported in association with triptans. The comparative tolerability of available agents for the abortive treatment of migraine attacks has not yet been systematically reviewed and quantified. Methods We performed a systematic literature review and Bayesian network meta-analysis for comparative tolerability of treatments for migraine. The literature search targeted all randomized controlled trials evaluating oral abortive treatments for acute migraine over a range of available doses in adults. The primary outcomes of interest were any adverse event, treatment-related adverse events, and serious adverse events. Secondary outcomes were fatigue, dizziness, chest discomfort, somnolence, nausea, and vomiting. Results Our search yielded 141 trials covering 15 distinct treatments. Of the triptans, sumatriptan, eletriptan, rizatriptan, zolmitriptan, and the combination treatment of sumatriptan and naproxen were associated with a statistically significant increase in odds of any adverse event or a treatment-related adverse event occurring compared with placebo. Of the non-triptans, only acetaminophen was associated with a statistically significant increase in odds of an adverse event occurring when compared with placebo. Overall, triptans were not associated with increased odds of serious adverse events occurring and the same was the case for non-triptans. For the secondary outcomes, with the exception of vomiting, all triptans except for almotriptan and frovatriptan were significantly associated with increased risk for all outcomes. Almotriptan was significantly associated with an increased risk of vomiting, whereas all other triptans yielded non-significant lower odds compared with placebo. Generally, the non-triptans were not associated with decreased tolerability for the secondary outcomes. Discussion In summary, triptans were associated with higher odds of any adverse event or a treatment-related adverse event occurring when compared to placebo and non-triptans. Non-significant results for non-triptans indicate that these treatments are comparable with one another and placebo regarding tolerability outcomes.

Background: Current antiretroviral therapy (ART) used to treat human immunodeficiency virus (HIV) patients is life-long because it only suppresses de novo infections. Recent efforts to eliminate HIV have tested the ability of a number of agents to reactivate ('Kick') the well-known latent reservoir. This approach is rooted in the assumption that once these cells are reactivated the host's immune system itself will eliminate ('Kill') the virus. While many agents have been shown to reactivate large quantities of the latent reservoir, the impact on the size of the latent reservoir has been negligible. This suggests that the immune system is not sufficient to eliminate reactivated reservoirs. Thus, there is a need for more emphasis on 'kill' strategies in HIV cure research, and how these might work in combination with current or future kick strategies., Methods: We conducted a landscape review of HIV 'cure' clinical trials using 'kick and kill' approaches. We identified and reviewed current available clinical trial results in human participants as well as ongoing and planned clinical trials. We dichotomized trials by whether they did not include or include a 'kill' agent. We extracted potential reasons why the 'kill' is missing from current 'kick and kill' strategies. We subsequently summarized and reviewed current 'kill' strategies have entered the phase of clinical trial testing in human participants and highlighted those with the greatest promise., Results: The identified 'kick' trials only showed promise on surrogate measures activating latent T-cells, but did not show any positive effects on clinical 'cure' measures. Of the 'kill' agents currently being tested in clinical trials, early results have shown small but meaningful proportions of participants remaining off ART for several months with broadly neutralizing antibodies, as well as agents for regulating immune cell responses. A similar result was also recently observed in a trial combining a conventional 'kick' with a vaccine immune booster ('kill')., Conclusion: While an understanding of the efficacy of each individual component is crucial, no single 'kick' or 'kill' agent is likely to be a fully effective cure. Rather, the solution is likely found in a combination of multiple 'kick and kill' interventions.

Objective: The objectives of this study were to evaluate the current state of reporting and handling of effect modification in network meta-analyses (NMAs) and perform exploratory analyses to identify variables that are potentially associated with incomplete reporting of effect modifiers in NMAs., Study Design and Setting: We conducted a meta-epidemiological survey using a systematic review of NMAs published in 2013 and identified through MEDLINE and Embase databases., Results: The review identified 77 NMAs. The most common type of effect modifiers identified and explored were patient characteristics (50.7% or 39/77), and the most common adjustment method used was sensitivity analysis (51.7% or 30/58). Over 45% (35/77) of studies did not describe a plan, nearly 40% (30/77) did not report the results of analyses, and approximately 47% (36/77) of studies had incomplete reporting. Exploratory univariate regression analyses yielded a statistically significant association for the variables of journal impact factor, ratio of randomized controlled trials to number of comparisons, and total number of randomized controlled trials., Conclusion: Current reporting practices are largely deficient, given that almost half of identified published NMAs do not explore or report effect modification. Journal impact factor and amount of available information in a network were associated with completeness of reporting., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To compare the safety profiles of TheraSphere ® (glass) and SIR-Spheres ® (resin) Y90 microspheres for the treatment of hepatocellular carcinoma. A systematic review was conducted using the databases MEDLINE, Embase, and Cochrane Trials Register to identify all relevant studies. Baseline characteristics and adverse events of all grades related to gastrointestinal, hepatobiliary, and respiratory systems were collected along with commonly reported outcomes related to post-embolization syndrome. For all outcomes, data from each study were tabulated for each intervention. Adverse events and patients were summed across studies on TheraSphere ® and SIR-Spheres ® , respectively, and the resulting proportion of patients experiencing an outcome for both interventions was calculated. Thirty-one observational studies were included in the review. In the adverse events of all grades, more patients treated with resin microspheres reported gastric ulcers, hepatic encephalopathy, cholecystitis, hepatic failure, and pleural effusion. Patients treated with resin microspheres also had more hepatobiliary adverse events of grade 3 or higher. In the events related to post-embolization syndrome, glass microspheres exhibited a similar safety profile compared to resin microspheres. Ascites and nausea grade 3 or higher were recorded more frequently with glass microsphere treatment. Based on this review of the published literature, glass microspheres exhibit a safety profile with fewer gastrointestinal and pulmonary adverse events compared to resin microspheres in the treatment of hepatocellular carcinoma.

Objective: To understand the severity and potential impact of heterogeneity in definitions of hypoglycemia used in diabetes research, we aimed to review the hypoglycemia definitions adopted in randomized controlled trials (RCTs)., Methods: We reviewed 109 RCTs included in the Canadian Agency for Drugs and Technologies in Health reports for the second- and third-line therapy for the patients with type 2 diabetes (T2D)., Results: Nearly 60% (n=66) of the studies reviewed presented the definitions for overall hypoglycemia, and another 20% (n=22) of the studies reported the results for hypoglycemia but did not report a definition. Among these 66 studies, only 9 (14%) followed the American Diabetes Association/European Medicines Agency specified guidelines to define hypoglycemia, with an exact threshold of plasma glucose ≤3.9 mmol/L. Fifty-two of the 66 studies (79%) used a threshold considerably lower than the recommended ≤3.9 mmol/L, and 16 studies used a threshold between 3.8 and 4.0 mmol/L. The proportion of the trials that used a cutoff value of <3.1 mmol/L appeared to be slightly similar among the more commonly used non-insulin treatments, GLP-1s (7 of 18 [39%]), thiazolidinediones (TZDs; 6 of 11 [55%]), DPP-4s (12 of 19 [64%]), and sulfonylureas (11 of 20 [55%]). Among trials with intermediate-long-acting insulins (neutral protamine Hagedorn insulin, detemir, glargine), 7 of 26 trials (27%) used a cutoff of <3.1 mmol/L. The definition of severe hypoglycemia was also subject to substantial heterogeneity, in both the utilized threshold and accompanying soft definitions., Conclusion: This review demonstrates that substantial heterogeneity exists in the definition of overall, severe/major, and nocturnal hypoglycemia across RCTs investigating T2D interventions., Competing Interests: Disclosure Funding for this study was granted by a Mitacs Elevate postdoctoral fellowship provided to CB. This fellowship allowed for the collaboration between researchers at Simon Fraser University and Precision Health Economics. ED, GS, KT, and EJM were employees of Precision Health Economics at the time of manuscript submission. MJ is a professor at Simon Fraser University. The authors report no other conflicts of interest in this work.

Aim: To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas (SUs) vs other glucose lowering drugs in patients with T2DM (T2DM)., Materials and Methods: A systematic review of Medline, Embase, Cochrane and clinicaltrials.gov was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios (HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used., Results: The systematic review identified 82 randomized controlled trials (RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined (HR 1.26, 95% confidence interval [CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors (HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin., Conclusions: The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs., (© 2016 John Wiley & Sons Ltd.)

Background: High adherence to antiretroviral therapy is crucial to the success of HIV treatment. We evaluated comparative effectiveness of adherence interventions with the aim of informing the WHO's global guidance on interventions to increase adherence., Methods: For this systematic review and network meta-analysis, we searched for randomised controlled trials of interventions that aimed to improve adherence to antiretroviral therapy regimens in populations with HIV. We searched Cochrane Central Register of Controlled Trials, Embase, and MEDLINE for reports published up to July 16, 2015, and searched major conference abstracts from Jan 1, 2013, to July 16, 2015. We extracted data from eligible studies for study characteristics, interventions, patients' characteristics at baseline, and outcomes for the study populations of interest. We used network meta-analyses to compare adherence and viral suppression for all study settings (global network) and for studies in low-income and middle-income countries only (LMIC network)., Findings: We obtained data from 85 trials with 16 271 participants. Short message service (SMS; text message) interventions were superior to standard of care in improving adherence in both the global network (odds ratio [OR] 1·48, 95% credible interval [CrI] 1·00-2·16) and in the LMIC network (1·49, 1·04-2·09). Multiple interventions showed generally superior adherence to single interventions, indicating additive effects. For viral suppression, only cognitive behavioural therapy (1·46, 1·05-2·12) and supporter interventions (1·28, 1·01-1·71) were superior to standard of care in the global network; none of the interventions improved viral response in the LMIC network. For the global network, the time discrepancy (whether the study outcome was measured during or after intervention was withdrawn) was an effect modifier for both adherence to antiretroviral therapy (coefficient estimate -0·43, 95% CrI -0·75 to -0·11) and viral suppression (-0·48; -0·84 to -0·12), suggesting that the effects of interventions wane over time., Interpretation: Several interventions can improve adherence and viral suppression; generally, their estimated effects were modest and waned over time., Funding: WHO., (Copyright © 2017 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Background: The most commonly prescribed medications used to treat migraine acutely are single analgesics, ergots, opioids, and triptans. Due to varying mechanisms of action across drug classes, there is reason to believe that some classes may be less likely than others to elicit Medication Overuse Headache (MOH) than others. We therefore aimed to determine whether certain classes of acute migraine drugs are more likely to elicit MOH than others., Methods: A comprehensive systematic literature was conducted to identify studies of varying designs that reported on MOH within the considered treatment classes. Only studies that reported MOH according to the International Classification of Headache Disorders (ICHD) were considered. Since no causal comparative design studies were identified; data from prevalence studies and surveys were retrieved. Prevalence-based relative risks between treatment classes were calculated by integrating both medication overuse and medication use from published studies. For each pair wise comparison, pooled relative risks were calculated as the inverse variance weighted average., Results: A total of 29 studies informed the relative risk between treatment classes, all of which reported country-specific data. Five studies reported country-specific medication use data. For triptans versus analgesics the study relative risks generally favored triptans. The pooled relative risk was 0.65 (i.e., relative risk reduction of 35 %). For ergots versus analgesics, a similar trend was observed in favor of ergots with a relative risk of 0.41. For triptans versus ergots, the direction of effect was mixed, and the pooled relative risk was 1.07. Both triptans and ergots appeared favorable when compared to opioids, with pooled relative risks of 0.35 and 0.76, respectively. However, the evidence was limited for these comparisons. Analgesics and opioids also appeared to yield similar risk of MOH (pooled relative risk 1.09)., Conclusion: Our study suggests that in patients receiving acute migraine treatment, analgesics and opioids are associated with a higher risk of developing MOH compared with other treatments. These findings provide incentive for better monitoring of use of analgesics and opioids for treating acute migraine, and suggest possible clinical preference for use of so-called "migraine-specific" treatments, that is, triptans and ergots.

Introduction: It is unclear whether using peers can improve adherence to antiretroviral therapy (ART). To construct the World Health Organization's global guidance on adherence interventions, we conducted a systematic review and network meta-analysis to determine the effectiveness of using peers for achieving adequate adherence and viral suppression., Methods: We searched for randomized clinical trials of peer-based interventions to promote adherence to ART in HIV populations. We searched six electronic databases from inception to July 2015 and major conference abstracts within the last three years. We examined the outcomes of adherence and viral suppression among trials done worldwide and those specific to low- and middle-income countries (LMIC) using pairwise and network meta-analyses., Results and Discussion: Twenty-two trials met the inclusion criteria. We found similar results between pairwise and network meta-analyses, and between the global and LMIC settings. Peer supporter+Telephone was superior in improving adherence than standard-of-care in both the global network (odds-ratio [OR]=4.79, 95% credible intervals [CrI]: 1.02, 23.57) and the LMIC settings (OR=4.83, 95% CrI: 1.88, 13.55). Peer support alone, however, did not lead to improvement in ART adherence in both settings. For viral suppression, we found no difference of effects among interventions due to limited trials., Conclusions: Our analysis showed that peer support leads to modest improvement in adherence. These modest effects may be due to the fact that in many settings, particularly in LMICs, programmes already include peer supporters, adherence clubs and family disclosures for treatment support. Rather than introducing new interventions, a focus on improving the quality in the delivery of existing services may be a more practical and effective way to improve adherence to ART., Competing Interests: The authors do not have any competing interests.

Background: Second-generation antipsychotics are commonly prescribed for pediatric patients with schizophrenia and schizophrenia spectrum disorders despite their lack of approval for use in children. Although considered a safer alternative to first-generation antipsychotics, there is evidence to suggest that second-generation antipsychotics may be associated with some adverse events as well as an increase in prolactin levels. The purpose of this review is to examine the risk of prolactin-related adverse events in pediatric patients using antipsychotics and to quantify changes in prolactin for this population., Methods: Literature searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO databases, supplemented with review of select gray literature to identify both randomized controlled trials and observational studies on pediatric patients prescribed antipsychotic medications for schizophrenia or schizophrenia spectrum disorders. Using a narrative approach, data on adverse events were recorded and changes from baseline in prolactin were pooled, where possible, from the randomized trials. Change from baseline in prolactin was evaluated for each treatment, as well as in comparison to placebo and to other treatments. Where data was available, these changes were evaluated separately for male and female patients., Results: Six randomized controlled trials and five observational studies, all examining the effects of second-generation antipsychotics, were selected. Literature reporting the effects of risperidone, quetiapine, aripiprazole, olanzapine, and paliperidone was identified, with varying doses. Prolactin-related adverse events were sparsely reported across studies. In evidence gathered from randomized controlled trials, risperidone, olanzapine, and two doses of paliperidone (3-5 mg/day and 6-12 mg/day) were associated with increased prolactin levels compared to baseline. With the exception of paliperidone, similar trends were observed in males and females, separately. The findings of the observational evidence served to both complement and run contrary to the randomized trials, with discrepancies attributed to differences in patient and treatment characteristics., Conclusions: No definitive conclusions between second-generation antipsychotic use and prolactin-related adverse events can be made based on the available literature. While some trends in prolactin level changes emerged, this was based on few trials with small sample sizes. Future investigations should emphasize reporting on treatment safety., Trial Registration: PROSPERO CRD42014009506 .

Background: New antiretroviral therapy (ART) regimens for HIV could improve clinical outcomes for patients. To inform global guidelines, we aimed to assess the comparative effectiveness of recommended ART regimens for HIV in ART-naive patients., Methods: For this systematic review and network meta-analysis, we searched for randomised clinical trials published up to July 5, 2015, comparing recommended antiretroviral regimens in treatment-naive adults and adolescents (aged 12 years or older) with HIV. We extracted data on trial and patient characteristics, and the following primary outcomes: viral suppression, mortality, AIDS defining illnesses, discontinuations, discontinuations due to adverse events, and serious adverse events. We synthesised data using network meta-analyses in a Bayesian framework and included older treatments, such as indinavir, to serve as connecting nodes. We defined network nodes in terms of specific antivirals rather than specific ART regimens. We categorised backbone regimens and adjusted for them through group-specific meta-regression. We used the GRADE framework to interpret the strength of inference., Findings: We identified 5865 citations through database searches and other sources, of which, 126 articles related to 71 unique trials were included in the network analysis, including 34 032 patients randomly assigned to 161 treatment groups. For viral suppression at 48 weeks, compared with efavirenz, the odds ratio (OR) for viral suppression was 1·87 (95% credible interval [CrI] 1·34-2·64) with dolutegravir and 1·40 (1·02-1·96) with raltegravir; with respect to viral suppression, low-dose efavirenz was similar to all other treatments. Both low-dose efavirenz and integrase strand transfer inhibitors tended to be protective of discontinuations due to adverse events relative to normal-dose efavirenz. The most protective effect relative to efavirenz in network meta-analyses was that of dolutegravir (OR 0·26, 95% CrI 0·14-0·47), followed by low-dose efavirenz (0·39, 0·16-0·92). Owing to insufficient data, we could make no conclusions about serious adverse events. Low event rates also limited the quality of evidence with regard to mortality and AIDS defining illnesses., Interpretation: The efficacy and safety of ART has substantially improved with the introduction of newer drug classes of antiretrovirals that are now available to patients and HIV care providers. Their improved tolerance could be part of a larger solution to improve retention, which is a challenge, particularly in low-income and middle-income country settings., Funding: The World Health Organization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Many published meta-analyses are underpowered. We explored the role of trial sequential analysis (TSA) in assessing the reliability of conclusions in underpowered meta-analyses., Methods: We screened The Cochrane Database of Systematic Reviews and selected 100 meta-analyses with a binary outcome, a negative result and sufficient power. We defined a negative result as one where the 95% CI for the effect included 1.00, a positive result as one where the 95% CI did not include 1.00, and sufficient power as the required information size for 80% power, 5% type 1 error, relative risk reduction of 10% or number needed to treat of 100, and control event proportion and heterogeneity taken from the included studies. We re-conducted the meta-analyses, using conventional cumulative techniques, to measure how many false positives would have occurred if these meta-analyses had been updated after each new trial. For each false positive, we performed TSA, using three different approaches., Results: We screened 4736 systematic reviews to find 100 meta-analyses that fulfilled our inclusion criteria. Using conventional cumulative meta-analysis, false positives were present in seven of the meta-analyses (7%, 95% CI 3% to 14%), occurring more than once in three. The total number of false positives was 14 and TSA prevented 13 of these (93%, 95% CI 68% to 98%). In a post hoc analysis, we found that Cochrane meta-analyses that are negative are 1.67 times more likely to be updated (95% CI 0.92 to 2.68) than those that are positive., Conclusions: We found false positives in 7% (95% CI 3% to 14%) of the included meta-analyses. Owing to limitations of external validity and to the decreased likelihood of updating positive meta-analyses, the true proportion of false positives in meta-analysis is probably higher. TSA prevented 93% of the false positives (95% CI 68% to 98%)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Divigel and Estrogel are estradiol gels for the treatment of postmenopausal women with moderate to severe vasomotor symptoms. They differ with respect to several factors including estradiol concentration and surface application, and cannot be compared solely on the basis of their estradiol dose. No randomized clinical trials have compared them head to head, but both have been compared with placebo. Therefore, the objective of this study was to conduct a systematic review and network meta-analysis of the two estradiol gels., Methods: We performed a comprehensive systematic literature review. One publication reporting on one Divigel trial, three publications reporting on two Estrogel trials, and five publications reporting on other estradiol transdermal preparations were identified. Efficacy outcomes were change from baseline in daily hot flush frequency and change from baseline in daily hot flush severity. Safety outcomes were frequency of treatment-related adverse events (AEs) and frequency of treatment-emergent AEs leading to discontinuation. Bayesian indirect treatment comparison meta-analysis of trial-level data was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research, Academy of Managed Care Pharmacy, National Pharmaceutical Council (ISPOR-AMCP-NPC) Good Practice Questionnaire. All outcomes were compared with respect to doses of the considered preparations., Results: For hot flush frequency, Divigel 0.25 mg was similar to Divigel 0.5 mg and to Estrogel 0.75 mg, and was statistically significantly superior to Estrogel 1.5 mg. The largest effect was observed with Divigel 1.0 mg (mean difference of 3.91 hot flushes/wk vs placebo), and was statistically significantly superior to all other interventions. The 1.5 mg Estrogel dose was associated with the smallest estimate of efficacy. For hot flush severity, Divigel 0.25 mg was similar to the efficacy of Divigel 0.5 mg, and for 0.25 mg and 0.5 mg of other estradiol gels, but was statistically inferior to Divigel 1.0 mg, Estrogel 0.75 mg, Estrogel 1.5 mg, and the 1.0 and 1.5 mg doses of all other estradiol gels. The estimated efficacy of Divigel 0.5 mg was similar to that of Estrogel 0.75 mg, Estrogel 1.5 mg, and the 0.25 and 0.5 mg doses of other transdermal estradiol preparations. Risks of treatment-related AEs for Divigel 0.25 mg, Divigel 0.5 mg, Estrogel 0.75 mg, and Estrogel 1.5 mg were similar and all were of a slightly higher risk than placebo. Among these, Divigel 1.0 mg, Estrogel 1.5 mg, and other gels 0.5 mg were statistically significantly less safe than placebo. However, for treatment-emergent AEs leading to discontinuation, none of the gels were associated with statistically significantly higher relative risks compared with placebo. In this study, statistically significant refers to the 95% credible intervals used in the Bayesian Network Analysis., Conclusions: Using network meta-analysis for indirect treatment comparison, we have shown that the efficacy of Divigel 0.25 mg, as measured by reduced hot flush frequency and severity, was similar to that of Divigel 0.5 mg and of Estrogel 0.75 and 1.5 mg. Overall, our analysis showed that Divigel 1.0 mg provided the best efficacy profile, but that this treatment was also associated with a higher risk of AEs. The network meta-analysis also showed that treatment with Estrogel 1.5 mg was associated with the smallest estimate of reduction in frequency of hot flushes.

Objective: To investigate whether liver metastases contribute to metastatic spread of colorectal cancer (CRC) by shedding intact tumor cells., Background: Metastases represent the primary cause of death in CRC. Understanding the metastatic activity of metastases and which patients are at high risk for tumor cell dissemination may, therefore, have significant influence on cancer care in the future., Methods: Circulating tumor cells (CTCs) were detected in the hepatic inflow (portal venous blood [PVB]) and outflow compartment (hepatic venous blood [HVB]) of a training (n = 55) and validation (n = 50) set using the CellSearch system. Isolated CTC from the HVB were subjected to gene expression analyses by quantitative polymerase chain reaction., Results: CTC detection rate (37.2% vs 19.6%; P = 0.04) and count (mean: 12.7, SEM: ± 5.9 vs 1.9; ± 1.2; P = 0.01) were significantly higher in HVB compared to PVB. The increased CTC detection rate (54% vs 11.4%; P < 0.001) and CTC count (14.7 ± 5.1 vs 1.1 ± 0.6; P < 0.001) in the HVB compared to the PVB compartment was confirmed in the validation cohort. Expression of epithelial markers and genes involved in cell-to-cell and cell-to-matrix adhesion was reduced in CTC compared to tumor cells in liver metastases. Metastasis size greater than 5 cm was associated with CTC shedding from established liver metastases in the training and validation cohorts., Conclusions: Colorectal liver metastases shed intact tumor cells with an invasive phenotype. Metastasis size serves as a surrogate marker for metastatic activity of colorectal liver metastases.

Purpose: Despite continuously improving therapies, gastric cancer still shows poor survival in locally advanced stages with local recurrence rates of up to 50% and peritoneal recurrence rates of 17% after curative surgery. We performed a systematic review with meta-analyses to clarify whether positive intraperitoneal cytology (IPC) indicates a high risk of disease recurrence and poor overall survival in gastric cancer., Methods: Multiple databases were searched in December 2014 to identify studies on the prognostic significance of positive intraperitoneal cytology in gastric cancer, including: Medline, Biosis, Science Citation Index, Embase, CCMed and publisher databases. Hazard ratios (HR) and associated 95% confidence intervals (CI) were extracted from the identified studies. A meta-analysis was performed using a random-effects model on overall survival, disease-free survival and peritoneal recurrence free survival., Results: A total of 64 studies with a cumulative sample size of 12,883 patients were included. Cytology, quantitative real time polymerase chain reaction (PCR) or both were performed in 35; 21 and 8 studies, respectively. Meta analyses revealed free intraperitoneal tumor cells (FITC) to be associated with poor overall survival in univariate (HR 3.27; 95% CI 2.82 - 3.78]) and multivariate (HR 2.45; 95% CI 2.04 - 2.94) analysis and poor peritoneal recurrence free survival in univariate (4.15; 95% CI 3.10 - 5.57) and multivariate (3.09; 95% CI 2.02 - 4.71) analysis. Subgroup analysis showed this effect to be independent of the detection method, Western or Asian origin or the time of publication., Conclusions: FITC oder positive peritoneal cytology is associated with poor survival and increased peritoneal recurrence in gastric cancer.

Determining the quality of a randomized clinical trial (RCT) is necessary for decision-makers to determine the believability and applicability of the trial findings. Issues that are likely to affect the utility of RCT evidence include issues of bias, random error and applicability. In this article we focus primarily on issues of bias and examine the evidence for whether reporting methodological items, including allocation concealment, sequence generation, and blinding of participants can be relied upon as evidence of bias. We present the findings of a systematic review of meta-epidemiological studies and a simulation study demonstrating that commonly examined sources of bias likely play little role in treatment exaggeration. We discuss other issues that may additionally influence trial outcomes including sample size, publication bias, and expertise of trialists. We conclude by discussing strategies to moderate the effect of known biases in assessing overall estimates of treatment effects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Although a reduced aflibercept (2.0 mg) injection frequency relative to the approved dosing posology is included in national treatment guidelines for wet age-related macular degeneration (AMD), there is limited evidence of its comparative efficacy. The objective was to compare the efficacy and safety of reduced frequency dosing for aflibercept, relative to other approved and marketed vascular endothelial growth factor inhibitors for wet AMD, over 12 months., Research Design and Methods: Based on a systematic literature review performed according to a pre-specified protocol, a Bayesian network meta-analysis (NMA) was conducted to indirectly compare posologies of aflibercept and ranibizumab (0.5 mg). The efficacy outcome, mean change from baseline in best-corrected visual acuity (BCVA) on the ETDRS chart, was evaluated at 3 and 12 months; and safety data at 12 months. Standard NMA models were used to analyze change at 3 months, and fractional polynomial regression over 12 months. Safety data were analyzed using binomial models with a logistic link function., Results: Five trials formed a complete evidence network. At 3 months, all posologies of aflibercept and ranibizumab resulted in similar changes in BCVA. Over 12 months, approved posologies of aflibercept and ranibizumab resulted in similar changes from baseline, between 6.7 (95% credible interval [CrI], 5.5, 7.8) and 9.1 (8.1, 10.1) ETDRS letters; however, reduced frequency aflibercept was associated with a smaller change (1.8 letters, [-25.9, 29.2]). There was a trend towards a greater change in BCVA, with increasing frequency of dosing. All posologies performed similarly with respect to safety, and CrIs were wide., Conclusions: Approved posologies of ranibizumab and aflibercept are similarly effective treatments for wet AMD. Reduced frequency aflibercept was associated with the poorest visual outcomes, and sample sizes were small. Findings from these analyses provide novel evidence of the comparative efficacy and safety of aflibercept and ranibizumab for wet AMD.

Background: Continued debate exists about whether initiation of antiretroviral therapy (ART) in symptom-free patients at higher baseline CD4 cell counts results in important clinical benefits. We aimed to examine to what extent baseline CD4 cell count at linkage to HIV care and at ART initiation predicts mortality in adults with HIV in Rwanda., Methods: We included data for patients with HIV in Rwanda who were aged 15 years or older and linked to care or initiated ART between Jan 1, 1997, and April 30, 2014, from nationally representative databases. We analysed the effect on mortality of baseline CD4 cell count at ART initiation and at linkage to care. Follow-up time was measured from time of ART initiation and from linkage to HIV care to study exit. To account for effect modification by time, we stratified by era of linkage (before 2008 vs 2008 or after) and for other indications for initiation of ART. We also stratified CD4 cell count by indication to initiate ART other than CD4 cell count status. We used Cox proportional hazard regressions to examine the effect of CD4 cell count at linkage and at ART initiation on mortality., Findings: Our analysis was based on data from 50,147 patients who initiated ART and 72,061 patients linked to care. In the late era (2008 and after), linkage to care at a CD4 cell count of 100-199 cells per μL without any further indication was associated with higher mortality than linkage at 200-349 cells per μL (hazard ratio [HR] 1·37, 95% CI 0·95-1·97); the effect was much the same for initiation of ART in this CD4 stratum (1·37, 0·92-2·04). For higher CD4 strata, linkage to care at 500 cells per μL or more was protective (0·53, 0·39-0·72), whereas the reported effect of initiation of ART on mortality was not distinguishable from chance alone (0·82, 0·21-3·20)., Interpretation: Efforts are needed to link and retain patients early in pre-ART HIV care. In settings where ART is not yet available for immediate treatment, retention in a strong pre-ART programme is effective at improving survival., Funding: The Bill & Melinda Gates Foundation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Canadian inflammatory bowel disease patients treated with infliximab are predominantly managed through a nationwide case management system, named BioAdvance(®)., Methods: A web-based survey was provided to patients currently receiving infliximab therapy within BioAdvance(®). Patients were categorized according to health trajectories: decliners, non-changers, moderate increasers and strong increasers. Factors associated with health trajectories were identified using multivariable multinomial logistic regression., Results: 918 of 1160 respondents were inflammatory bowel disease patients reporting health status. Strong increasers were more likely to use educational tools than non-changers (adjusted odds ratio [aOR]: 1.65; 95% CI: 1.03-2.64), to be treated for ulcerative colitis (aOR: 2.05; 95% CI: 1.16-3.64) and to perceive case management as important (aOR: 2.52; 95% CI: 1.56-4.09). Younger (aOR: 0.72; 95% CI: 0.63-0.83) and French-speaking (aOR: 0.34; 95% CI: 0.18-0.63) patients were less likely to miss workdays. Patients were more likely to have missed workdays prior to joining the case management program., Conclusions: Inflammatory bowel disease patients receiving infliximab within the nationwide case management system report a positive impact on health status and absenteeism.

The PRISMA statement is a reporting guideline designed to improve the completeness of reporting of systematic reviews and meta-analyses. Authors have used this guideline worldwide to prepare their reviews for publication. In the past, these reports typically compared 2 treatment alternatives. With the evolution of systematic reviews that compare multiple treatments, some of them only indirectly, authors face novel challenges for conducting and reporting their reviews. This extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement was developed specifically to improve the reporting of systematic reviews incorporating network meta-analyses. A group of experts participated in a systematic review, Delphi survey, and face-to-face discussion and consensus meeting to establish new checklist items for this extension statement. Current PRISMA items were also clarified. A modified, 32-item PRISMA extension checklist was developed to address what the group considered to be immediately relevant to the reporting of network meta-analyses. This document presents the extension and provides examples of good reporting, as well as elaborations regarding the rationale for new checklist items and the modification of previously existing items from the PRISMA statement. It also highlights educational information related to key considerations in the practice of network meta-analysis. The target audience includes authors and readers of network meta-analyses, as well as journal editors and peer reviewers.

Objective: To determine the short-term costs per sustained remission and sustained response of three tumor necrosis factor inhibitors (infliximab, adalimumab, and golimumab) in comparison to conventional therapy for the treatment of moderately-to-severely active ulcerative colitis., Methods: A probabilistic Markov model was developed. This included an 8-week induction period, and 22 subsequent 2-week cycles (up to 1 year). The model included three disease states: remission, response, and relapse. Costs were from a Canadian public payer perspective. Estimates for the additional cost per 1 year of sustained remission and sustained response were obtained., Results: Golimumab 100 mg provided the lowest cost per additional remission ($935) and cost per additional response ($701) compared with conventional therapy. Golimumab 50 mg yielded slightly higher costs than golimumab 100 mg. Infliximab was associated with the largest additional number of estimated remissions and responses, but also higher cost at $1975 per remission and $1311 per response. Adalimumab was associated with the largest cost per remission ($7430) and cost per response ($2361). The cost per additional remission and cost per additional response associated with infliximab vs golimumab 100 mg was $14,659 and $4753, respectively., Conclusions: The results suggest that the additional cost of 1 full year of remission and response are lowest with golimumab 100 mg, followed by golimumab 50 mg. Although infliximab has the highest efficacy, it did not exhibit the lowest cost per additional remission or response. Adalimumab produced the highest cost per additional remission and response.

Aim: To conduct a network meta-analysis (NMA) to establish the comparative efficacy of infliximab, adalimumab and golimumab for the treatment of moderately to severely active ulcerative colitis (UC)., Design: A systematic literature search identified five randomized controlled trials for inclusion in the NMA. One trial assessed golimumab, two assessed infliximab and two assessed adalimumab. Outcomes included clinical response, clinical remission, mucosal healing, sustained clinical response and sustained clinical remission. Innovative methods were used to allow inclusion of the golimumab trial data given the alternative design of this trial (i.e., two-stage re-randomization)., Results: After induction, no statistically significant differences were found between golimumab and adalimumab or between golimumab and infliximab. Infliximab was statistically superior to adalimumab after induction for all outcomes and treatment ranking suggested infliximab as the superior treatment for induction. Golimumab and infliximab were associated with similar efficacy for achieving maintained clinical remission and sustained clinical remission, whereas adalimumab was not significantly better than placebo for sustained clinical remission. Golimumab and infliximab were also associated with similar efficacy for achieving maintained clinical response, sustained clinical response and mucosal healing. Finally, golimumab 50 and 100 mg was statistically superior to adalimumab for clinical response and sustained clinical response, and golimumab 100 mg was also statistically superior to adalimumab for mucosal healing., Conclusion: The results of our NMA suggest that infliximab was statistically superior to adalimumab after induction, and that golimumab was statistically superior to adalimumab for sustained outcomes. Golimumab and infliximab appeared comparable in efficacy.

Objectives: To establish the comparative efficacy and safety of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in older adults using the network meta-analysis approach., Design: Systematic review and network meta-analysis., Participants: Individuals aged 60 and older., Measurements: Data on partial response (defined as at least 50% reduction in depression score from baseline) and safety (dizziness, vertigo, syncope, falls, loss of consciousness) were extracted. A Bayesian network meta-analysis was performed on the efficacy and safety outcomes, and relative risks (RRs) with 95% credible intervals (CrIs) were produced., Results: Fifteen randomized controlled trials were eligible for inclusion in the analysis. Citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, fluoxetine, and sertraline were represented. Reporting on partial response and dizziness was sufficient to conduct a network meta-analysis. Reporting on other outcomes was sparse. For partial response, sertraline (RR=1.28), paroxetine (RR=1.48), and duloxetine (RR=1.62) were significantly better than placebo. The remaining interventions yielded RRs lower than 1.20. For dizziness, duloxetine (RR=3.18) and venlafaxine (RR=2.94) were statistically significantly worse than placebo. Compared with placebo, sertraline had the lowest RR for dizziness (1.14) and fluoxetine the second lowest (1.31). Citalopram, escitalopram, and paroxetine all had RRs between 1.4 and 1.7., Conclusion: There was clear evidence of the effectiveness of sertraline, paroxetine, and duloxetine. There also appears to be a hierarchy of safety associated with the different antidepressants, although there appears to be a dearth of reporting of safety outcomes., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

Aim: To conduct a network meta-analysis (NMA) to determine the comparative efficacy, as measured by sustained virological response (SVR), between boceprevir (BOC), telaprevir (TEL), faldaprevir (FAL), simeprevir (SIM) and sofosbuvir (SOF) in combination with peginterferon-ribavirin (PR) against a control of PR., Design: A literature search was conducted to identify randomized controlled trials (RCTs) including adult patients with hepatitis C virus genotype 1 who were naive to any prior therapy. RCTs assessing standard duration therapy (SDT) or response-guided therapy (RGT) BOC, TEL, FAL, SIM or SOF in combination with PR against a control of PR were eligible for inclusion. All RCTs must have provided SVR at either 12 or 24 weeks post-therapy cessation., Results: We included nine RCTs. All direct-acting antivirals (DAAs) were found to perform better than PR. Additionally, SDT FAL was found to be better than the 240 mg RGT FAL regimen with the PR lead-in. A sensitivity analysis excluding RCTs with only SVR at 12 weeks was consistent with the results of the primary analysis. A sensitivity analysis removing an RCT assessing SIM that reported SVR of >60% in the PR control group additionally found that RGT SIM was superior to the 240 mg RGT FAL regimen with the PR lead-in., Discussion: Our analyses indicate that SDT and RGT regimens of DAAs plus PR do not differ greatly in terms of SVR among treatment-naive hepatitis C genotype 1 patients. More advanced Bayesian network meta-analyses are likely needed to incorporate a comprehensive evidence base, expanding beyond randomized clinical trials., (© The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)