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Journal of Clinical Epidemiology Dec 2023To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to...
OBJECTIVES
To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes.
STUDY DESIGN AND SETTING
Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting. We grouped reported outcomes thematically and classified them following the COMET Initiative's taxonomy. We describe instruments used for assessing each outcome.
RESULTS
We found 280 eligible RCTs of which 115 (41.1%) enrolled critically ill patients and 165 (58.9%) predominantly noncritically ill patients. We identified 43 distinct outcomes and 108 measurement instruments, excluding nonvalidated scores and questionnaires. Almost all trials reported clinical/physiological outcomes (97.5%). Safety (63.2%), mortality (56.4%), resource use (48.6%) and life impact (11.8%) outcomes were less frequently addressed. The most frequently reported outcomes were treatment success (60.7%), mortality (56.4%) and adverse events (41.1%). There was significant variation in the selection of measurement instruments, with approximately two-thirds used in less than 10 of the 280 RCTs. None of the patient-reported outcomes were used in 10 or more RCTs.
CONCLUSION
This review reveals significant variation in outcomes and measurement instruments reported in clinical trials of pneumonia management. Outcomes that are important to patients and health professionals are often omitted. Our findings support the need for a rigorous core outcome set, such as that being developed by the European Respiratory Society.
Topics: Adult; Humans; Pneumonia; Treatment Outcome; Clinical Trials as Topic
PubMed: 37898460
DOI: 10.1016/j.jclinepi.2023.10.011 -
Journal of Clinical Pharmacology Nov 2016During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully... (Review)
Review
During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean C and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.
Topics: Adult; Age Factors; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Discovery; Humans; Pharmaceutical Preparations; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 27040726
DOI: 10.1002/jcph.744 -
The Cochrane Database of Systematic... Jun 2017Dry eye syndrome is a disorder of the tear film that is associated with symptoms of ocular discomfort. Punctal occlusion is a mechanical treatment that blocks the tear... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Dry eye syndrome is a disorder of the tear film that is associated with symptoms of ocular discomfort. Punctal occlusion is a mechanical treatment that blocks the tear drainage system in order to aid in the preservation of natural tears on the ocular surface.
OBJECTIVES
To assess the effects of punctal plugs versus no punctal plugs, different types of punctal plugs, and other interventions for managing dry eye.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 11), MEDLINE Ovid (1946 to 8 December 2016), Embase.com (1947 to 8 December 2016), PubMed (1948 to 8 December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 8 December 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com; last searched 18 November 2012 - this resource is now archived), ClinicalTrials.gov (www.clinicaltrials.gov; searched 8 December 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en; searched 8 December 2016). We did not use any date or language restrictions in the electronic searches for trials. We also searched the Science Citation Index-Expanded database and reference lists of included studies. The evidence was last updated on 8 December 2016 SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials of collagen or silicone punctal plugs in symptomatic participants diagnosed with aqueous tear deficiency or dry eye syndrome.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trial quality and extracted data. We contacted study investigators for additional information when needed.
MAIN RESULTS
We included 18 trials (711 participants, 1249 eyes) from Austria, Canada, China, Greece, Japan, Mexico, Netherlands, Turkey, the UK, and the USA in this review. We also identified one ongoing trial. Overall we judged these trials to be at unclear risk of bias because they were poorly reported. We assessed the evidence for eight comparisons.Five trials compared punctal plugs with no punctal plugs (control). Three of these trials employed a sham treatment and two trials observed the control group. Two trials did not report outcome data relevant to this review. There was very low-certainty evidence on symptomatic improvement. The three trials that reported this outcome used different scales to measure symptoms. In all three trials, there was little or no improvement in symptom scores with punctal plugs compared with no punctal plugs. Low-certainty evidence from one trial suggested less ocular surface staining in the punctal plug group compared with the no punctal plug group however this difference was small and possibly clinically unimportant (mean difference (MD) in fluorescein staining score -1.50 points, 95% CI -1.88 to -1.12; eyes = 61). Similarly there was a small difference in tear film stability with people in the punctal plug group having more stability (MD 1.93 seconds more, 95% CI 0.67 to 3.20; eyes = 28, low-certainty evidence). The number of artificial tear applications was lower in the punctal plug group compared with the no punctal plugs group in one trial (MD -2.70 applications, 95% CI -3.11 to -2.29; eyes = 61, low-certainty evidence). One trial with low-certainty evidence reported little or no difference between the groups in Schirmer scores, but did not report any quantitative data on aqueous tear production. Very low-certainty evidence on adverse events suggested that events occurred reasonably frequently in the punctal plug group and included epiphora, itching, tenderness and swelling of lids with mucous discharge, and plug displacement.One trial compared punctal plugs with cyclosporine (20 eyes) and one trial compared punctal plugs with oral pilocarpine (55 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.Five trials compared punctal plugs with artificial tears. In one of the trials punctal plugs was combined with artificial tears and compared with artificial tears alone. There was very low-certainty evidence on symptomatic improvement. Low-certainty evidence of little or no improvement in ocular surface staining comparing punctal plugs with artificial tears (MD right eye 0.10 points higher, 0.56 lower to 0.76 higher, MD left eye 0.60 points higher, 0.10 to 1.10 higher) and low-certainty evidence of little or no difference in aqueous tear production (MD 0.00 mm/5 min, 0.33 lower to 0.33 higher)Three trials compared punctal plugs in the upper versus the lower puncta, and none of them reported the review outcomes at long-term follow-up. One trial with very low-certainty evidence reported no observed complications, but it was unclear which complications were collected.One trial compared acrylic punctal plugs with silicone punctal plugs and the trial reported outcomes at approximately 11 weeks of follow-up (36 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.One trial compared intracanalicular punctal plugs with silicone punctal plugs at three months follow-up (57 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.Finally, two trials with very low-certainty evidence compared collagen punctal plugs versus silicone punctal plugs (98 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.
AUTHORS' CONCLUSIONS
Although the investigators of the individual trials concluded that punctal plugs are an effective means for treating dry eye signs and symptoms, the evidence in this systematic review suggests that improvements in symptoms and commonly tested dry eye signs are inconclusive. Despite the inclusion of 11 additional trials, the findings of this updated review are consistent with the previous review published in 2010. The type of punctal plug investigated, the type and severity of dry eye being treated, and heterogeneity in trial methodology confounds our ability to make decisive statements regarding the effectiveness of punctal plug use. Although punctal plugs are believed to be relatively safe, their use is commonly associated with epiphora and, less commonly, with inflammatory conditions such as dacryocystitis.
Topics: Dry Eye Syndromes; Female; Humans; Lacrimal Apparatus; Male; Punctal Plugs; Randomized Controlled Trials as Topic; Tears; Treatment Outcome
PubMed: 28649802
DOI: 10.1002/14651858.CD006775.pub3 -
Regional Anesthesia and Pain Medicine 2016We summarized the evidence for ultrasound (US) guidance for truncal blocks in 2010 by performing a systematic literature review and rating the strength of evidence for... (Review)
Review
UNLABELLED
We summarized the evidence for ultrasound (US) guidance for truncal blocks in 2010 by performing a systematic literature review and rating the strength of evidence for each block using a system developed by the United States Agency for Health Care Policy and Research. Since then, numerous studies of US guidance for truncal blocks have been published. In addition, 3 novel US-guided blocks have been described since our last review. To provide updated recommendations, we performed another systematic search of the literature to identify studies pertaining to US guidance for the following blocks: paravertebral, intercostal, transversus abdominis plane, rectus sheath, ilioinguinal/iliohypogastric, as well as the Pecs, quadratus lumborum, and transversalis fascia blocks. We rated the methodologic quality of each of the identified studies and then graded the strength of evidence supporting the use of US for each block based on the number and quality of available studies for that block.
WHAT'S NEW
Since our last review, numerous studies have been published, especially for the paravertebral and transversus abdominis plane blocks, and 3 novel US-guided blocks (Pecs, quadratus lumborum, and transversalis fascia blocks) have been described. Although some of these studies support the use of US for performing these blocks, others do not. Additional studies have used US to improve our understanding of the anatomy pertinent to these blocks and evaluated the effect on patient outcomes and risk of complications.
Topics: Abdominal Muscles; Clinical Trials as Topic; Evidence-Based Medicine; Humans; Nerve Block; Pain, Postoperative; Ultrasonography, Interventional
PubMed: 26866299
DOI: 10.1097/AAP.0000000000000372 -
PloS One 2017The aim of this systematic review was to document efficacy, safety and quality of evidence of analgesic interventions after total knee arthroplasty (TKA). (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The aim of this systematic review was to document efficacy, safety and quality of evidence of analgesic interventions after total knee arthroplasty (TKA).
METHODS
This PRISMA-compliant and PROSPERO-registered review includes all-language randomized controlled trials of medication-based analgesic interventions after TKA. Bias was evaluated according to Cochrane methodology. Outcomes were opioid consumption (primary), pain scores at rest and during mobilization, adverse events, and length of stay. Interventions investigated in three or more trials were meta-analysed. Outcomes were evaluated using forest plots, Grading of Recommendations Assessment, Development and Evaluation (GRADE), L'Abbe Plots and trial sequential analysis.
RESULTS
The included 113 trials, investigating 37 different analgesic interventions, were characterized by unclear/high risk of bias, low assay sensitivity and considerable differences in pain assessment tools, basic analgesic regimens, and reporting of adverse events. In meta-analyses single and continuous femoral nerve block (FNB), intrathecal morphine, local infiltration analgesia, intraarticular injection of local anaesthetics, non-steroidal anti-inflammatory drugs, and gabapentinoids demonstrated significant analgesic effects. The 24-hour morphine-sparing effects ranged from 4.2 mg (CI: 1.3, 7.2; intraarticular local anaesthetics), to 16.6 mg (CI: 11.2, 22; single FNB). Pain relieving effects at rest at 6 hours ranged from 4 mm (CI: -10, 2; gabapentinoids), to 19 mm (CI: 8, 31; single FNB), and at 24 hours from 3 mm (CI: -2, 8; gabapentinoids), to 16 mm (CI: 8, 23; continuous FNB). GRADE-rated quality of evidence was generally low.
CONCLUSION
A low quality of evidence, small sample sizes and heterogeneity of trial designs prohibit designation of an optimal procedure-specific analgesic regimen after TKA.
Topics: Arthroplasty, Replacement, Knee; Clinical Trials as Topic; Combined Modality Therapy; Humans; Pain Management; Pain Measurement; Pain, Postoperative; Treatment Outcome
PubMed: 28273133
DOI: 10.1371/journal.pone.0173107 -
BJOG : An International Journal of... Jun 2017Progestogens have been evaluated in numerous trials and meta-analyses, many of which concluded they were effective. However, two large trials PROMISE and OPPTIMUM have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Progestogens have been evaluated in numerous trials and meta-analyses, many of which concluded they were effective. However, two large trials PROMISE and OPPTIMUM have recently concluded that progesterone was ineffective. This raises the possibility that earlier studies and reviews had been biased by either selective publication or selective choice of outcomes, so called "P-hacking".
OBJECTIVES
To compare the findings all progestogen trials and systematic reviews with those of trials with pre-registered primary outcomes which avoided selective outcome reporting.
SEARCH STRATEGY
Search of PubMed, the Cochrane Library and trial registries. Registration PROSPERO CRD42016035303.
SELECTION CRITERIA
Systematic reviews of randomised trials comparing progestogen with placebo in pregnancy and the individual trials included in those reviews. The subset of trials reporting a pre-registered primary outcome were compared with the totality of trials and reviews.
DATA COLLECTION AND ANALYSIS
For reviews all outcomes were included. For individual trials all outcomes reported in the systematic reviews were included. For the comparison group we recorded the registered primary outcome from trials that were either registered before they started, or registered during the recruitment phase and also double blind.
MAIN RESULTS
Nineteen of twenty-nine meta-analyses concluded that progestogens were effective. Twenty-two trials reported their pre-registered primary outcomes. There was no effect of progesterone on primary registered dichotomous outcome RR 1.00 (95% CI 0.94-1.07). Only one of the 22 showed a nominally statistically significant benefit.
AUTHOR'S CONCLUSIONS
When evaluated in registered double-blind trials with analysis restricted to predefined primary outcomes, progestational agents in pregnancy are ineffective.
TWEETABLE ABSTRACT
Progestogens to prevent pregnancy loss, an example of P-hacking.
Topics: Female; Humans; Pregnancy; Bias; Clinical Trials as Topic; Pregnancy Complications; Pregnancy Outcome; Progesterone; Research Design; Systematic Reviews as Topic
PubMed: 28318099
DOI: 10.1111/1471-0528.14506 -
Inflammatory Bowel Diseases Apr 2024Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials.
METHODS
MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated.
RESULTS
In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes.
CONCLUSIONS
Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.
Topics: Humans; Crohn Disease; Endoscopy; Remission Induction; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 37002875
DOI: 10.1093/ibd/izad052 -
Trials Nov 2015Tuberculosis (TB) remains a major killer amongst the infectious diseases. Current treatment involves a four-drug regimen for at least 6 months. New drugs and regimens... (Meta-Analysis)
Meta-Analysis Review
Tuberculosis (TB) remains a major killer amongst the infectious diseases. Current treatment involves a four-drug regimen for at least 6 months. New drugs and regimens are required to shorten treatment duration, reduce toxicity and combat drug resistance, but the optimal methodology to define the critical path for novel regimens is not well defined. We undertook a systematic review to summarise outcomes reported in Phase II trials of patients with newly diagnosed pulmonary TB to assess the need for a core outcome set. A systematic search of databases (PubMed, MEDLINE, EMBASE and LILACs) was conducted on 1 May 2015 to retrieve relevant peer-reviewed articles. Reference lists of included studies were also searched. This systematic review considered all reported outcomes. Risk of bias was considered via sequence generation, allocation concealment, blinding, reasons for exclusions, and selective reporting. Of 55 included studies, 20 were Phase IIB studies based on culture conversion, 32 were Phase IIA studies based on quantitative bacteriology, and three considered alternative outcomes. Large variation in reported outcomes and trial characteristics was observed across the included studies. Bacteriological results were as often expressed in terms of positivity as negativity, with varying definitions of culture conversion. Variation in reporting was particularly marked for Phase IIA studies, where multiple time intervals were typically selected for analysis and sometimes resulted in differing interpretations of the efficacy of drugs or regimens. Within both Phase IIA and IIB studies, there was variation in the time points at which the study participants were sampled, as well as in the bacteriological media and methods used. For successful future meta-analysis of early-phase studies, the findings of this review suggest that development of a core outcome set would be desirable. This would enable trial results to be more easily compared and combined, potentially leading to more effective development of new treatment strategies for patients with TB. Pending development of, and agreement on, such a core outcome set, we suggest some interim recommendations for reporting of future phase II studies of pulmonary tuberculosis.
Topics: Antitubercular Agents; Bacteriological Techniques; Clinical Trials, Phase II as Topic; Drug Resistance, Bacterial; Endpoint Determination; Humans; Predictive Value of Tests; Quality Control; Randomized Controlled Trials as Topic; Research Design; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary
PubMed: 26566930
DOI: 10.1186/s13063-015-1050-1 -
Rheumatology (Oxford, England) Sep 2017SSc is clinically and pathogenetically heterogeneous. Consensus standards for trial design and outcome measures are needed. International experts experienced in SSc... (Review)
Review
SSc is clinically and pathogenetically heterogeneous. Consensus standards for trial design and outcome measures are needed. International experts experienced in SSc clinical trial design and a researcher experienced in systematic literature review screened the PubMed and Cochrane Central Register of Controlled Trials in order to develop points to consider when planning a clinical trial for muscle involvement in SSc. The experts conclude that SSc-associated muscle involvement is heterogeneous and lacks a universally accepted gold-standard for measuring therapeutic response. Although outcome studies are currently limited by the inability to clearly distinguish active, reversible muscle inflammation from irreversible muscle damage and extramuscular organ involvement, strong consideration should be given to enrolling patients with a myopathy that features several elements of likely reversibility such as muscle weakness, biopsy-proven active inflammation, an MRI indicating muscle inflammation and a baseline serum creatinine kinase above three times the upper limit of normal to prevent floor effect. Randomized controlled trials are preferred, with a duration of at least 24 weeks. Outcome measures should include a combination of elements that are likely to be reversible, such as muscle weakness, biopsy-proven active inflammation, creatinine kinase/aldolase and a quality of life questionnaire. The individual measurements might require a short pre-study for further validation. A biological sample repository is recommended.
Topics: Clinical Trials as Topic; Disease Management; Humans; Muscular Diseases; Scleroderma, Systemic
PubMed: 28992167
DOI: 10.1093/rheumatology/kex196 -
Dermatology (Basel, Switzerland) 2023Hidradenitis suppurativa (HS) is a chronic inflammatory disease that disproportionally affects women, as well as Black and biracial individuals. While adalimumab remains...
BACKGROUND
Hidradenitis suppurativa (HS) is a chronic inflammatory disease that disproportionally affects women, as well as Black and biracial individuals. While adalimumab remains the only therapy approved by the Food and Drug Administration for HS, many HS clinical trials for novel and re-tasked therapies are ongoing or upcoming. To optimize treatment equity, reflect the patient population, and facilitate trial participation, it is important to elucidate aspects of clinical trial protocols that may systematically exclude specific patient groups or impose hardships.
OBJECTIVE
The study aimed to systematically review inclusion and exclusion criteria as well as participant demographics in HS clinical trials.
METHODS
A literature search of PubMed, Embase, Cochrane Central, and Web of Science databases was conducted. Peer-reviewed publications of randomized controlled trials that were written in English and had at least 10 participants were included. Title and abstract screening and data extraction were completed by two independent reviewers, with disagreements resolved by a third.
RESULTS
Twenty-three studies totaling 1,496 adult participants met the inclusion criteria. Race and ethnicity were not reported in 473/1,496 (31.6%) and 1,420/1,496 (94.9%) trial participants, respectively. Trial participants were predominantly white (811/1,023, 79.3%) and female (1,057/1,457, 72.5%). The median of each study's average age was 35.7 years (IQR 33.5-38.0), and 17/23 (73.9%) trials excluded pediatric patients. Nearly all participants had Hurley Stage II (499/958, 52.0%) or Hurley Stage III (385/958, 40.2%) disease. Many trials excluded patients who were pregnant (19/23, 82.6%) and breastfeeding (13/23, 56.5%), or who had HS that was "too severe" (8/23, 34.8%) or "too mild" (16/23, 70.0%). Frequently, trial protocols required prolonged washout periods from HS therapies, relatively long duration in the study's placebo arm, and prohibited concurrent analgesic use.
CONCLUSIONS
This systematic review of 23 HS clinical trials totaling 1,496 participants identified substantial hardships imposed by trial participation, high rates of missing race and ethnicity data, and low representation of key patient groups, including those who identify as Black. Future trials with pragmatic study designs, broader inclusion criteria, and study sites in diverse communities may alleviate burdens of trial participation and improve enrollment of diverse patient groups.
Topics: Adult; Humans; Female; Hidradenitis Suppurativa; Clinical Trials as Topic; Adalimumab; Demography; Randomized Controlled Trials as Topic
PubMed: 36108592
DOI: 10.1159/000526069