Phase-3 Randomized Controlled Trials on Exclusion of Participants With Kidney Disease in COVID-19.
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ABSTRACT:
SUBMITTER: Chewcharat A
PROVIDER: S-EPMC7577277 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Phase-3 Randomized Controlled Trials on Exclusion of Participants With Kidney Disease in COVID-19.
Chewcharat Api A Chang Yuan-Ting YT Sise Meghan E ME Bhattacharyya Roby P RP Murray Megan B MB Nigwekar Sagar U SU
Kidney international reports 20201021 1
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Project description:ObjectivePost-randomisation exclusions in randomised controlled trials are common and may include participants identified as not meeting trial eligibility criteria after randomisation. We report how a decision might be reached and reported on, to include or exclude these participants. We illustrate using a motivating scenario from the BREATHE trial (Trial registration ClinicalTrials.gov, NCT02426112) evaluating azithromycin for the treatment of chronic lung disease in people aged 6-19 years with HIV in Zimbabwe and Malawi.Key pointsIncluding all enrolled and randomised participants in the primary analysis of a trial ensures an unbiased estimate of the intervention effect using intention-to-treat principles, and minimises the effects of confounding through balanced allocation to trial arm. Ineligible participants are sometimes enrolled, due to measurement or human error. Of 347 participants enrolled into the BREATHE trial, 11 (3.2%) were subsequently found to be ineligible based on lung function criteria. We assumed no safety risk of azithromycin treatment; their inclusion in the trial and subsequent analysis of the intervention effect therefore mirrors clinical practice. Senior trial investigators considered diurnal variations in the measurement of lung function, advantages of retaining a higher sample size and advice from the Data Safety and Monitoring Board and Trial Steering Committee, and decided to include these participants in primary analysis. We planned and reported analyses including and excluding these participants, and in our case the interpretation of treatment effect was consistent.ConclusionThe decision, by senior investigators, on whether to exclude enrolled participants, should reflect issues of safety, treatment efficacy, statistical power and measurement error. As long as decisions are made prior to finalising the statistical analysis plan for the trial, the risk of exclusions creating bias should be minimal. The decision taken should be transparently reported and a sensitivity analysis can present the opposite decision.
| S-EPMC7713189 | biostudies-literature
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Project description:BackgroundEndpoint choice for randomized controlled trials of treatments for novel coronavirus-induced disease (COVID-19) is complex. Trials must start rapidly to identify treatments that can be used as part of the outbreak response, in the midst of considerable uncertainty and limited information. COVID-19 presentation is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks to over a month and can end in death. While improvement in mortality would provide unquestionable evidence about the clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical, particularly given a multitude of putative therapies to evaluate. Furthermore, patient states in between "cure" and "death" represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly given the variable time course of COVID-19. Outcomes measured at fixed time points, such as a comparison of severity scores between treatment and control at day 14, may risk missing the time of clinical benefit. An endpoint such as time to improvement (or recovery) avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of "recovered" versus "not recovered."MethodsWe evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials.ResultsPower for fixed time-point methods depends heavily on the time selected for evaluation. Time-to-event approaches have reasonable statistical power, even when compared with a fixed time-point method evaluated at the optimal time.DiscussionTime-to-event analysis methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses.
| S-EPMC7611901 | biostudies-literature
Project description:BackgroundIn the context of the COVID-19 pandemic, randomized controlled trials (RCTs) are essential to support clinical decision-making. We aimed (1) to assess and compare the reporting characteristics of RCTs between preprints and peer-reviewed publications and (2) to assess whether reporting improves after the peer review process for all preprints subsequently published in peer-reviewed journals.MethodsWe searched the Cochrane COVID-19 Study Register and L·OVE COVID-19 platform to identify all reports of RCTs assessing pharmacological treatments of COVID-19, up to May 2021. We extracted indicators of transparency (e.g., trial registration, data sharing intentions) and assessed the completeness of reporting (i.e., some important CONSORT items, conflict of interest, ethical approval) using a standardized data extraction form. We also identified paired reports published in preprint and peer-reviewed publications.ResultsWe identified 251 trial reports: 121 (48%) were first published in peer-reviewed journals, and 130 (52%) were first published as preprints. Transparency was poor. About half of trials were prospectively registered (n = 140, 56%); 38% (n = 95) made their full protocols available, and 29% (n = 72) provided access to their statistical analysis plan report. A data sharing statement was reported in 68% (n = 170) of the reports of which 91% stated their willingness to share. Completeness of reporting was low: only 32% (n = 81) of trials completely defined the pre-specified primary outcome measures; 57% (n = 143) reported the process of allocation concealment. Overall, 51% (n = 127) adequately reported the results for the primary outcomes while only 14% (n = 36) of trials adequately described harms. Primary outcome(s) reported in trial registries and published reports were inconsistent in 49% (n = 104) of trials; of them, only 15% (n = 16) disclosed outcome switching in the report. There were no major differences between preprints and peer-reviewed publications. Of the 130 RCTs published as preprints, 78 were subsequently published in a peer-reviewed journal. There was no major improvement after the journal peer review process for most items.ConclusionsTransparency, completeness, and consistency of reporting of COVID-19 clinical trials were insufficient both in preprints and peer-reviewed publications. A comparison of paired reports published in preprint and peer-reviewed publication did not indicate major improvement.
| S-EPMC9510360 | biostudies-literature
Project description:Several vaccines have been approved for the prevention of COVID-19. However, no head-to-head trials comparing their clinical efficacy have been performed. This network meta-analysis aims to identify those, among the competing existing vaccines, conferring the maximum protection against COVID-19. A literature search was done in Medline (via PubMed), Embase and Cochrane Library databases for phase 3 randomized controlled trials evaluating the efficacy of different COVID-19 vaccines. Search results were screened and eligible studies were included to perform a network meta-analysis in software 'R' version 4.1.2 using a random effect model. Cochrane's 'Risk of Bias tool (RoB2)' was used for quality assessment. Raw data from the included studies was used for network meta-analysis. Assessment of inconsistency was not possible as no study compared two or more vaccines directly. A forest plot for indirect comparison of various COVID-19 vaccines was obtained. Rankogram and 'P' scores were obtained to rank the vaccines based on the indirect evidence of their comparative efficacy. A total of 17 randomized controlled trials evaluating the efficacy of 16 COVID-19 vaccines, were included in the network meta-analysis. A total of 361,386 participants was included in this network meta-analysis. Overall risk of bias among included studies was of 'some concern'. All the COVID-19 vaccines had a statistically significant reduction of risk for contracting symptomatic SARS-CoV-2 in comparison to the placebo, however, the maximum protection (RR 0.05) was with BNT126b2. The indirect comparison also revealed BNT126b2 vaccine confers the highest protection against symptomatic SARS-CoV-2 infection in comparison to all others included, with a 'P' score of 0.9771 followed by mRNA-1273, rAD26 & rAD5 and NVX-CoV2373. The evidence generated from this network meta-analysis indicates the good efficacy of all the included vaccines in preventing symptomatic COVID-19 as compared to placebo. The BNT126b2 vaccine was found to provide the highest protection against symptomatic SARS-CoV-2 among all included followed by mRNA-1273, rAD26 & rAD5, NVX-CoV2373 and others.
| S-EPMC9640819 | biostudies-literature
Project description: Not available
| S-EPMC8733489 | biostudies-literature
Project description:Prevalence of Parkinson's disease (PD) increases with age. The purpose of this study was to evaluate the eligibility criteria in randomized clinical trials (RCTs) in PD, especially those limiting the enrollment of older adults. We examined RCTs of pharmacological and non-pharmacological anti-parkinsonian interventions registered with ClinicalTrials.gov and started from 2013 through 2022. Primary outcome was proportion of RCTs with an upper age limit of 85 years of age or less. Secondary outcome was proportion of RCTs with other exclusion criteria. Associations between trial characteristics and the presence of the age limits were determined using logistic regression. Our study included 420 RCTs. Two hundred thirty-nine (57%) of these had an upper age limit of 85 years of age or less. Proportion of these trials significantly increased over time. The odds of the presence of an upper age limit were significantly associated with the investigational site location, phase, and timeframe for the primary endpoint assessment. Three hundred fifty-six (85%) trials had other eligibility criteria limiting the enrollment of older patients; these often (n = 285; 68%) included cognitive impairment. Overall, 386 (92%) RCTs either explicitly excluded older adults or had criteria indirectly limiting their enrollment. Underrepresentation of older patients in clinical trials in PD considerably reduces the generalizability of their results. Some eligibility criteria should be modified to enable the investigators to assess the benefits and harms of new therapeutic interventions in older adults. This problem is important in view of rapidly growing number of older patients with PD.
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Project description:Delaying disease progression and reducing the risk of mortality are key goals in the treatment of chronic kidney disease (CKD). New drug classes to augment renin-angiotensin-aldosterone system (RAAS) inhibitors as the standard of care have scarcely met their primary endpoints until recently. This systematic literature review explored treatments evaluated in patients with CKD since 1990 to understand what contemporary data add to the treatment landscape. Eighty-nine clinical trials were identified that had enrolled patients with estimated glomerular filtration rate 13.9-102.8 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 29.9-2911.0 mg/g, with (75.5%) and without (20.6%) type 2 diabetes (T2D). Clinically objective outcomes of kidney failure and all-cause mortality (ACM) were reported in 32 and 64 trials, respectively. Significant reductions (P < 0.05) in the risk of kidney failure were observed in seven trials: five small trials published before 2008 had evaluated the RAAS inhibitors losartan, benazepril, or ramipril in patients with (n = 751) or without (n = 84-436) T2D; two larger trials (n = 2152-2202) published onwards of 2019 had evaluated the sodium-glucose co-transporter 2 (SGLT2) inhibitors canagliflozin (in patients with T2D and UACR > 300-5000 mg/g) and dapagliflozin (in patients with or without T2D and UACR 200-5000 mg/g) added to a background of RAAS inhibition. Significant reductions in ACM were observed with dapagliflozin in the DAPA-CKD trial. Contemporary data therefore suggest that augmenting RAAS inhibitors with new drug classes has the potential to improve clinical outcomes in a broad range of patients with CKD.
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Project description:The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) altered the logistics of ongoing randomized controlled trials (RCTs). The need to reduce in-person research and clinical activities, however, presented an additional level of complexity in order to continue conducting RCTs that focused on the development of medications for Alcohol Use Disorder (AUD). The visits required a systematic objective evaluation from the physician and mental health professional and clinical staff, as many of the safety and efficacy assessments are self-reported. The following commentary addresses the successes and limitations our RCTs encountered during the coronavirus (COVID-19) pandemic.
| S-EPMC7832637 | biostudies-literature
Project description:IntroductionAs the global epidemic continues to spread, countries have tapped effective drugs to treat new coronavirus pneumonia. The therapeutic effect of the traditional Chinese medicine Lianhua Qingwen in this new coronary pneumonia epidemic has attracted attention from all walks of life, and relevant research reports continue to appear. Therefore, we conducted a systematic review of the clinical efficacy and safety of the traditional Chinese medicine Lianhua Qingwen in the treatment of new coronavirus pneumonia (COVID-19) (referred to as "new coronary pneumonia"), and evaluated the overall level of research quality.MethodsWe searched seven databases and retrieved the Chinese Journal Full-text Database (CNKI), Vip Database (VIP), China Biomedicine (SinoMed), Wanfang Database and PubMed, Cochrane Central, EMBASE from October 2019 to May 2020 Literature references. We included randomized controlled trials (RCTs) that tested the efficacy of the traditional Chinese medicine lotus clearing plague in the treatment of new coronavirus pneumonia. The authors extracted data and independently assessed quality. We used Stata15.1 software to analyze the data of randomized trials.ResultsA total of 2 articles were identified, including 154 patients. All the participating patients were diagnosed with new coronavirus pneumonia (COVID-19). The meta-analysis results showed that the disappearance rate of the main clinical symptoms of Chinese medicine Lianhua Qingwen in the treatment of new coronavirus pneumonia was significantly higher than that of the control group [OR = 3.34, 95% CI (2.06, 5.44), P <0.001]; the disappearance rate of other clinical secondary symptoms is significantly higher than the control group [OR = 6.54, 95% CI (3.59, 11.90), P <0.001]. The duration of fever was significantly lower than that of the control group [OR = -1.04, 95% CI (-1.60, -0.49), P <0.001]. It is confirmed that the traditional Chinese medicine Lianhua Qingwen treatment improves the clinical effectiveness, and also has certain advantages in relieving cough and fever.ConclusionThe treatment of new pneumonia with traditional Chinese medicine lotus clearing plague can be used as an effective therapy to improve the clinical symptoms of new coronary pneumonia. More rigorous design, multi-center, and prospective RCTs are necessary to further determine the effectiveness and safety of the traditional Chinese medicine lotus decoction in the treatment of new pneumonia.
| S-EPMC7485773 | biostudies-literature