Clinical trials design and conduct Henderson, William G.
Biostatistics & epidemiology (Oxford, UK),
20/1/1/, Volume:
4, Issue:
1
Journal Article
Peer reviewed
This article attempts to outline the most important aspects to consider when planning a randomized controlled clinical trial (RCT) and writing a proposal for the RCT. RCTs are generally formulated by ...a planning committee that should be comprised of members with expertise in the different important features of the trial. Important considerations include background, objectives/hypotheses, experimental design, patient population and recruitment/retention plan, stratification/randomization, experimental treatment, control or comparison treatment, blinding, primary and secondary outcomes, patient follow-up, data to be collected, capture of data and confidentiality, handling of adverse events, sample size/statistical power and feasibility, statistical analysis, ethical issues, and governance of the trial. Real world examples, mostly drawn from the US Department of Veterans Affairs Cooperative Studies Program, are used to illustrate the various important considerations.
Neurokinin receptor 1 antagonists are effective in reducing nausea and vomiting in chemotherapy-induced emesis. We investigated the safety and efficacy of tradipitant, a neurokinin receptor 1 ...antagonist, in patients with idiopathic and diabetic gastroparesis.
A total of 201 adults with gastroparesis were randomly assigned to oral tradipitant 85 mg (n = 102) or placebo (n = 99) twice daily for 12 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. Blood levels were monitored for an exposure-response analysis. The primary outcome was change from baseline to week 12 in average nausea severity, measured by daily symptom diary.
The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12 (difference in nausea severity change drug vs placebo; P = .741) or prespecified secondary endpoints. Post hoc analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation. Subjects with high blood levels of tradipitant significantly improved average nausea severity beginning at early time points (weeks 2–4). In post hoc sensitivity analyses, tradipitant treatment demonstrated strengthened effects, with statistically significant improvements in nausea at week 12.
Although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. When accounting for confounding factors such as baseline severity inflation and rescue medication, a statistically significant effect was also observed. These findings suggest that tradipitant has potential as a treatment for the symptom of nausea in gastroparesis. (ClincialTrials.gov, Number: NCT04028492).
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Patients with haemodialysis catheters are susceptible to dialysis-associated infections, particularly bloodstream infections. There have been few systematic attempts to reduce this burden. Our study ...aimed to investigate the effect of a multimodal prevention strategy on dialysis-associated infection events (DAIE) among haemodialysis outpatients.
A multicentre, stepped wedge, cluster-randomized controlled trial was done from October 2019 to September 2021. Outpatient dialysis facilities entered into the intervention phase in three randomly assigned clusters, at three predefined time points. The multimodal prevention strategy consisted of infection surveillance and hand hygiene (HH) compliance observation with active feedback and teaching aseptic procedures, and a patient flyer.
The primary outcome was incidence rates of different DAIE, such as bloodstream infections, intravenous antimicrobial starts, and local access-site infections per 1000 dialysis. As secondary outcome, we analysed the HH compliance change.
A total of 43 haemodialysis outpatient facilities with 11 251 patients and 1 413 457 proceeded haemodialysis were included in the DIPS-trial. Incidence rates were 0.71 DAIE per 1000 dialysis (95% CI, 0.65–0.78) in the control and 0.31 (95% CI, 0.27–0.36) in the intervention group. The univariable analysis yielded an incidence rate ratio (IRR) of 0.44 (95% CI, 0.33–0.59) for DAIE. Especially in patients with a central venous catheter, we saw a significant decrease in DAIE in the intervention group (IRR 0.4; 95% CI, 0.28–0.58). The HH observation combined with feedback and intensified training, resulted in an increase of HH compliance from 58–65%.
A multimodal prevention strategy showed a significant preventive effect on DAIE among haemodialysis outpatients. This reduction also applied to bloodstream infections, especially in patients with a central venous catheter.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Gestational air pollution exposure may impact cardiometabolic health in childhood.•We evaluated air cleaner use during pregnancy and obesity-related outcomes in young children.•The intervention was ...associated with effects in the expected directions.•Reducing air pollution during pregnancy may improve children’s cardiometabolic health.
Gestational exposure to particulate matter (PM) air pollution may increase the risk of childhood obesity, but the impact of reducing air pollution during pregnancy on obesity-related outcomes in childhood has not been examined.
To assess the impact of reducing gestational PM exposure on body mass index (BMI) at two years of age.
In this single-blind, parallel group randomized controlled trial in Ulaanbaatar Mongolia, we randomly assigned 540 pregnant women to receive 1–2 portable high efficiency particulate air (HEPA) filter air cleaners or no air cleaners. We measured height and weight when children were a mean age of 23.8 months. Our primary outcome was age- and sex-specific BMI z-score based on the World Health Organization 2007 Growth Charts. Secondary outcomes included age- and sex-specific weight z score, overweight/obesity (defined as BMI z-score > 2.00), and catch-up growth (defined using various cut-offs to identify children with relatively low birth weight for sex and gestational age and relatively high age- and sex-specific weight in childhood). We imputed missing outcome data using multiple imputation with chained equations and our primary analysis was by intention to treat (ITT). We estimated intervention effects on continuous and binary outcomes using linear and logistic regression, respectively.
After excluding known miscarriages, still births, and neonatal deaths our analysis included 480 children (235 control and 245 intervention). The mean (SD) child BMI z score was 0.79 (1.0); 9.8% of children were overweight or obese. The mean BMI z score of children who were randomly assigned to the intervention group was 0.16-units lower (95% CI: −0.35, 0.04) than children in the control group. The intervention was also associated with reductions in overweight/obesity (odds ratio = 0.59; 95% CI: 0.31, 1.12). Catch-up growth occurred less frequently in the intervention group, but effect estimates varied depending on the specific definition of catch-up growth and confidence intervals consistently spanned no effect.
We found that the use of portable air cleaners during pregnancy was associated with improvements in obesity-related outcomes, although some effect estimates lacked precision. Reducing PM exposure during pregnancy may lead to improvements in cardiometabolic health in childhood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is a substantial unmet need for effective and patient-acceptable drugs to treat severe mental illnesses like schizophrenia. Computational analysis of genomic, transcriptomic, and pharmacologic ...data generated in the past two decades enables repurposing of drugs or compounds with acceptable safety profiles, namely those that are FDA-approved or reached late stages in clinical trials. We developed a rational approach to achieve this computationally for schizophrenia by studying drugs that target the proteins in its protein interaction network (‘interactome’). This involved contrasting the transcriptomic modulations observed in the disorder and the drug; our analyses resulted in 12 candidate drugs, 9 of which had additional supportive evidence: their target networks were enriched for pathways relevant to schizophrenia etiology or for genes that had an association with diseases pathogenically similar to schizophrenia. To translate these computational results to the clinic, these shortlisted drugs must be tested empirically through randomized controlled trials (RCT), where their prior safety approvals obviate the need for time-consuming phase I and II studies. We selected two among the shortlisted candidates based on likely adherence and side effect profiles. We are testing them through adjunctive RCTs for patients with schizophrenia or schizoaffective disorder who experienced incomplete resolution of psychotic features with conventional treatment. The integrated computational analysis for identifying and ranking drugs for clinical trials can be iterated as additional data are obtained. Our approach could be expanded to enable disease subtype-specific drug discovery in future and should also be exploited for other psychiatric disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To provide an overview of treatments in the pipeline for adults with attention-deficit/hyperactivity disorder (ADHD), we searched https://clinicaltrials.gov/and and ...https://www.clinicaltrialsregister.eu/ from 01/01/2010–10/18/2023 for ongoing or completed phase 2 or 3 randomised controlled trials (RCTs), assessing pharmacological or non-pharmacological interventions for adults with ADHD with no current regulatory approval. We found 90 eligible RCTs. Of these, 24 (27 %) reported results with statistical analysis for primary efficacy endpoints. While several pharmacological and non-pharmacological interventions had evidence of superiority compared to the control condition from a single RCT, centanafadine (norepinephrine, dopamine, and serotonin re-uptake inhibitor) was the only treatment with evidence of efficacy on ADHD core symptoms (small effect size=0.28–0.40) replicated in at least one additional RCT, alongside reasonable tolerability. Overall, the body of ongoing RCTs in adults with ADHD is insufficient, without any intervention on the horizon to match the efficacy of stimulant treatment or atomoxetine and with better tolerability profile. Additional effective and well tolerated treatments for adults with ADHD require development and testing.
•There is a need for additional treatments for ADHD in adults.•We found 90 relevant RCTs registered in the past decade.•Centanafadine was the only treatment with replicated evidence of efficacy (small).•Additional treatments for adults with ADHD should be developed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We conducted a systematic review and meta-analysis to quantify the effect of attention-deficit/hyperactivity disorder (ADHD) medication on quality of life (QoL), and to understand whether this effect ...differs between stimulants and non-stimulants.
From the dataset of a published network meta-analysis (Cortese et al., 20181), updated on 27th February 2023 (https://med-adhd.org/), we identified randomized controlled trials (RCTs) of ADHD medications for individuals aged 6 years or more with a diagnosis of ADHD based on the DSM (from third to fifth editions) or the International Classification of Diseases (ICD; ninth or tenth revision), reporting data on QoL (measured with a validated scale). The risk of bias for each RCTs was assessed using the Cochrane Risk of Bias tool 2. Multi-level meta-analytic models were conducted with R 4.3.1.
We included 17 RCTs (5,388 participants in total; 56% randomized to active medication) in the meta-analyses. We found that amphetamines (Hedges g = 0.51, 95% CI = 0.08, 0.94), methylphenidate (0.38; 0.23, 0.54), and atomoxetine (0.30; 0.19, 0.40) were significantly more efficacious than placebo in improving QoL in people with ADHD, with moderate effect size. For atomoxetine, these effects were not moderated by the length of intervention, and did not differ between children/adolescents and adults.
In addition to being efficacious in reducing ADHD core symptom severity, both stimulant and non-stimulant medications are efficacious in improving QoL in people with ADHD, albeit with lower effect sizes. Future research should explore whether, and to what degree, combining pharmacological and non-pharmacological interventions is likely to further improve QoL in people with ADHD.
Effects of pharmacological treatment for ADHD on quality of life: a systematic review and meta-analysis; https://osf.io/;qvgps.
Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain ...unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.
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•Venous and arterial thrombosis are prevalent in patients with COVID-19.•Optimal thromboprophylaxis has not been established for patients with this disease.•Numerous randomized trials are evaluating antithrombotic regimens for outpatients and inpatients with COVID-19.•Ongoing experience has influenced the design, conduct, analysis, and reporting the results of these trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Evidence on the optimal follow-up schedule after endometrial cancer is lacking. The study aim was to compare satisfaction with care between women who received reduced follow-up care and women who ...received usual guideline-directed follow-up care for three years after surgery.
The ENSURE (ENdometrial cancer SURvivors' follow-up carE) trial was a non-inferiority randomized controlled multicenter trial in 42 hospitals in the Netherlands. The intervention arm received reduced follow-up care (4 visits/3 years), while the control group received usual follow-up care (8–11 visits/3 years). Primary outcome was overall satisfaction with care, PSQIII score, over three years follow-up, with a non-inferiority margin of 6. Mixed linear regression, intention-to-treat and per-protocol analyses (presented below) were used.
Among 316 women included, overall satisfaction with care was not lower in the reduced follow-up (mean 82; SD = 15) compared with the usual follow-up group (mean 80; SD = 15) group (B = 1.80(−2.09;5.68)). At 6, 12 and 36 months, more women (93/94/90%) in the reduced follow-up group were satisfied with their follow-up schedule than in the usual follow-up group (79/79/82%; p < 0.001; p < 0.001; p = 0.050).
Women with low-risk, early-stage endometrial cancer who received reduced follow-up care were no less satisfied with their care than women receiving usual follow-up care. Compared with usual follow-up, women in the reduced follow-up group had fewer clinical visits and, at the same time, more often reported being satisfied with their follow-up schedule. Findings suggest that reduced follow-up care may be the new standard, but should be tailored to meet additional needs where indicated.
•Reduced follow-up does not compromise satisfaction with care or worry.•Patients prefer the schedule of reduced follow-up.•Reduced follow-up care may be the new standard for endometrial cancer.•Follow-up should be tailored to meet individual patient needs in case of worry.•Findings may be relevant for other low-risk cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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