Kristian Thorlund

McMaster University | McMaster

To date, two published randomized trials have indicated a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. Using the results of the largest of these trials, the TOGETHER trial, we conducted a cost-consequence analysis to assess the health system benefits of preventing progression to severe CO...

Introduction Bayesian adaptive designs for clinical trials have gained popularity in the recent years due to the flexibility and efficiency that they offer. We consider the scenario where the outcome of interest comprises events with relatively low risk of occurrence and different case definitions resulting in varying control group risk assumptions...

Fluvoxamine is widely prescribed as an antidepressant. Recent studies show the drug may have a clinical benefit in treating COVID-19. We aimed to perform a meta-analysis of the existing randomized trials of fluvoxamine compared with placebo on the early treatment of COVID-19 patients. We included only randomized clinical trials enrolling ambulatory...

Background Three randomized trials have been conducted indicating a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. We assessed the cost-consequences associated with the use of this early treatment in outpatient populations. Methods Using results from the three completed trials of fluvoxamin...

Introduction The German health technology assessment (HTA) rejected additional benefit of alectinib for second line (2L) ALK+ NSCLC, citing possible biases from missing ECOG performance status data and unmeasured confounding in real-world evidence (RWE) for 2L ceritinib that was submitted as a comparator to the single arm alectinib trial. Alectinib...

Importance Evidence regarding real-world effectiveness of therapies for patients with advanced non–small cell lung cancer (NSCLC) whose tumors are resistant to platinum-based chemotherapy is lacking. Objective To compare the effectiveness of the immune checkpoint inhibitors atezolizumab (programmed cell death ligand 1 inhibitor) and nivolumab (pro...

B ackground: There remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as treatments for early COVID-19 among outpatients at a high risk for severe complicat...

Importance: Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD). Objective: To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-sma...

Background: Although vaccines are currently available for coronavirus disease 2019 (COVID-19), there remains a need for an effective and affordable outpatient treatment for early COVID-19. Multiple repurposed drugs have shown promise in treating COVID-19. We describe a master protocol that will assess the efficacy of different repurposed drugs as t...

Evaluating whether an intervention works when trialled in groups of individuals can pose complex challenges for clinical research. Cluster randomised controlled trials involve the random allocation of groups or clusters of individuals to receive an intervention, and they are commonly used in global health research. In this paper, we describe the po...

In global health research, short-term, small-scale clinical trials with fixed, two-arm trial designs that generally do not allow for major changes throughout the trial are the most common study design. Building on the introductory paper of this Series, this paper discusses data-driven approaches to clinical trial research across several adaptive tr...

Background The 2018 World Health Organization HIV guidelines were based on the results of a network meta-analysis (NMA) of published trials. This study employed individual patient-level data (IPD) and aggregate data (AgD) and meta-regression methods to assess the evidence supporting the WHO recommendations and whether they needed any refinements....

Background The novel coronavirus 2019 (COVID-19) pandemic has mobilized global research at an unprecedented scale. While challenges associated with the COVID-19 trial landscape have been discussed previously, no comprehensive reviews have been conducted to assess the reporting, design, and data sharing practices of randomized controlled trials (RCT...

Background The use of individual patient data (IPD) in network meta-analyses (NMA) is rapidly growing. This study aimed to determine, through simulations, the impact of select factors on the validity and precision of NMA estimates when combining IPD and aggregate data (AgD) relative to using AgD only. Methods Three analysis strategies were compare...

The Bayesian paradigm provides an ideal platform to update uncertainties and carry them over into the future in the presence of data. Bayesian Predictive Power (BPP) reflects our belief in the eventual success of a clinical trial to meet its goals. In this paper we derive mathematical expressions for the most common types of outcomes, to make the B...

Background To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens. Methods We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinica...

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 comparati...

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, wate...

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 effect...

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. Met...

e20523 Background: Comparing the effectiveness of multiple myeloma treatments presents a challenge due to the limited number of head-to-head trials with which to conduct indirect treatment comparisons. This is particularly true when subgroup analysis is of interest. In comparative effectiveness research Simulated Treatment Comparisons (STCs) are be...

Background: In an effort to contain the COVID-19 epidemic, many governments across the world have enforced lockdown or social distancing measures. Several outbreak models have been developed to investigate the effects of different public health strategies for COVID-19, but they have not been developed for Pakistan and other South East Asian countri...

Kristian Thorlund,1,2 Louis Dron,2 Jay JH Park,2,3 Edward J Mills1,2 1Department of Health Research Methods, Evidence & Impact (HEI), McMaster University, Hamilton, ON, Canada; 2MTEK Sciences, Vancouver, BC, Canada; 3Department of Medicine, University of British Columbia, Vancouver, BC, CanadaCorrespondence: Kristian ThorlundMTEK Sciences, 802-777...

Objective 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 STAMPED...

Background: Myocardial injury after noncardiac surgery (MINS) is common and of prognostic importance. Little is known about MINS in orthopaedic surgery. The diagnostic criterion for MINS was a level of ≥0.03 ng/mL on a non-high-sensitivity troponin T (TnT) assay due to myocardial ischemia. Methods: We undertook an international, prospective stud...

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 an...

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 e...

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, wate...

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 comparat...

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 effect...

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 eval...

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...

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 evalu...

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 quant...

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 rep...

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 i...

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 und...

Background Master protocols, classified as basket trials, umbrella trials, and platform trials, are a novel approach that offers 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 published master protocols using...

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 prope...

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 prope...

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...

A statistical analysis plan for my one of my core thesis chapters.

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-an...

This article reviews important considerations for researchers who are designing adaptive clinical trials. These differ from conventional clinical trials because they allow and even enforce continual modifications to key components of trial design while data are being collected. This innovative approach has the potential to reduce resource use, decr...

Jay JH Park,1 Kristian Thorlund,2,3 Edward J Mills2,3 1Department of Medicine, University of British Columbia, Vancouver, BC, Canada; 2Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, ON, Canada; 3The Bill and Melinda Gates Foundation, Seattle, WA, USA Abstract: Adaptive clinical trials are an innova...

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 in...

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 onc...

Objective To evaluate the current state of reporting and handling of effect modification in network meta-analyses (NMAs), as well as 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 utilizing...

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...

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 gas...

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...

Use of peers to improve adherence to antiretroviral therapy: a global network meta-analysis

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 d...

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 a...

Aim: Our aim was to conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulfonylureas versus other antihyperglycaemic drugs in patients with type 2 diabetes. Materials and methods: A systematic review of Medline, Embase, Cochrane, and clinicaltrials.gov was conducte...

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 co...

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 tri...

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...

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...