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JAMA Dermatology Mar 2022There are knowledge gaps regarding the relative efficacy of 3 commonly used drugs for androgenetic alopecia (AGA), namely, minoxidil and the two 5-α reductase... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
There are knowledge gaps regarding the relative efficacy of 3 commonly used drugs for androgenetic alopecia (AGA), namely, minoxidil and the two 5-α reductase inhibitors dutasteride and finasteride.
OBJECTIVE
To examine the relative efficacy of any dose and administration route of minoxidil, dutasteride, and finasteride for the treatment of male AGA.
DATA SOURCES
Systematic searches were performed in PubMed on March 5, 2021, without date restrictions.
STUDY SELECTION
Eligible studies included those that investigated monotherapy with any dose and administration route of minoxidil, dutasteride, and finasteride.
DATA EXTRACTION AND SYNTHESIS
Data on the mean (SD) difference and sample size were used for the bayesian network meta-analyses. League tables and surface under the cumulative ranking curve values were used to examine the relative efficacy of the interventions.
MAIN OUTCOMES AND MEASURES
Study end points were change in total and terminal hair count after 24 and 48 weeks of therapy. The 4 end points were quantified in hairs per square centimeters.
RESULTS
The PubMed search yielded 848 records; after the 2 stages of screening, 23 studies were eligible for quantitative analyses. Mean (SD) age of patients ranged from 22.8 (3.3) years to 41.8 (12.3) years. The greatest increase in total hair count at 24 weeks (ie, first end point) was with 0.5 mg/d of dutasteride, which was significantly more efficacious than 1 mg/d of finasteride (mean difference, 7.1 hairs/cm2; 95% CI, 5.1-9.3 hairs/cm2) and minoxidil (0.25 mg/d [mean difference, 23.7 hairs/cm2; 95% CI, 9.5-38.0 hairs/cm2], 5 mg/d [mean difference, 15.0 hairs/cm2; 95% CI, 3.9-26.1 hairs/cm2], and 2% solution [mean difference, 8.5 hairs/cm2; 95% CI, 4.8-12.3 hairs/cm2]). The greatest increase in terminal hair count at 24 weeks (ie, second end point) was with 5 mg/d of minoxidil, which was significantly more efficacious than the 0.25-mg/d dose (mean difference, 43.6 hairs/cm2; 95% CI, 29.7-57.7 hairs/cm2) and its topical forms (in 2% [mean difference, 29.3 hairs/cm2; 95% CI, 21.1-37.5 hairs/cm2] and 5% [mean difference, 29.8 hairs/cm2; 95% CI, 19.7-39.8 hairs/cm2]); 5 mg/d of minoxidil was significantly more efficacious than 1 mg/d of finasteride (mean difference, 10.4 hairs/cm2; 95% CI, 2.2-18.6 hairs/cm2). The greatest increase in total hair count at 48 weeks (ie, third end point) was with 5 mg/d of finasteride, which was significantly more efficacious than 2% topical minoxidil (mean difference, 20.7 hairs/cm2; 95% CI, 9.5-31.9 hairs/cm2). The greatest increase in terminal hair count at 48 weeks (ie, fourth end point) was with 1 mg/d of finasteride, which was significantly more effective than topical minoxidil (in 2% [mean difference, 32.1 hairs/cm2; 95% CI, 23.9-40.3 hairs/cm2] and 5% [mean difference, 26.2 hairs/cm2; 95% CI, 16.2-36.2 hairs/cm2]).
CONCLUSIONS AND RELEVANCE
As efficacy data from head-to-head trials accumulate, there could be a better sense of the relative efficacy of the different doses of the 5-α reductase inhibitors and minoxidil. The findings of this meta-analysis contribute to the comparative effectiveness literature for AGA therapies with regard to the compared interventions.
Topics: 5-alpha Reductase Inhibitors; Adult; Alopecia; Bayes Theorem; Dutasteride; Finasteride; Humans; Male; Minoxidil; Network Meta-Analysis; Treatment Outcome; Young Adult
PubMed: 35107565
DOI: 10.1001/jamadermatol.2021.5743 -
Journal of the American Society of... Sep 2019Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits.
METHODS
To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point.
RESULTS
Across all studies, the treatment effect on 3-year total GFR slope (median =0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope ( 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability.
CONCLUSIONS
With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.
Topics: Bayes Theorem; Biomarkers; Creatinine; Disease Progression; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Predictive Value of Tests; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic
PubMed: 31292197
DOI: 10.1681/ASN.2019010007 -
JAMA Dermatology Jun 2023Safe and effective long-term treatments for adolescents with moderate to severe atopic dermatitis (AD) are limited. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Safe and effective long-term treatments for adolescents with moderate to severe atopic dermatitis (AD) are limited.
OBJECTIVE
To evaluate the efficacy and safety of interleukin-13-targeted treatment with tralokinumab monotherapy in adolescents with AD.
DESIGN, SETTING, AND PARTICIPANTS
The 52-week, randomized, double-blinded, placebo-controlled, phase 3 ECZTRA 6 trial was conducted from July 17, 2018, through March 16, 2021, at 72 centers across 10 countries in North America, Europe, Asia, and Australia. Enrolled patients were 12 to 17 years old with moderate to severe AD (Investigator's Global Assessment [IGA] score ≥3; Eczema Area and Severity Index [EASI] ≥16).
INTERVENTIONS
Patients were randomized (1:1:1) to tralokinumab (150 or 300 mg) or placebo every 2 weeks for 16 weeks. Patients with an IGA score of 0 (clear) or 1 (almost clear) and/or 75% or higher improvement in EASI (EASI 75) at week 16 without rescue medication received maintenance treatment; other patients switched to open-label tralokinumab, 300 mg, every 2 weeks.
MAIN OUTCOMES AND MEASURES
Primary end points at week 16 were an IGA score of 0 or 1 and/or achieving EASI 75. Key secondary end points were a reduction of Adolescent Worst Pruritus Numeric Rating Scale of 4 or more, change in SCORing AD, and change in Children's Dermatology Life Quality Index from baseline to week 16. Safety end points were the number of adverse events and serious adverse events.
RESULTS
Of 301 patients randomized, 289 comprised the full analysis set (median [IQR] age, 15.0 [13.0-16.0] years; 149 [51.6%] male). More patients receiving tralokinumab, 150 mg, (n = 98), and tralokinumab, 300 mg (n = 97), achieved an IGA score of 0 or 1 without rescue medication at week 16 (21 [21.4%] and 17 [17.5%], respectively) vs placebo (n = 94; 4 [4.3%]) (adjusted difference, 17.5% [95% CI, 8.4%-26.6%]; P < .001 and 13.8% [95% CI, 5.3%-22.3%]; P = .002, respectively). More patients receiving tralokinumab, 150 mg (28 [28.6%]), and tralokinumab, 300 mg, (27 [27.8%]) vs placebo (6 [6.4%]) achieved EASI 75 without rescue at week 16 (adjusted difference, 22.5% [95% CI, 12.4%-32.6%]; P < .001 and 22.0% [95% CI, 12.0%-32.0%]; P < .001, respectively). Proportions of patients with Adolescent Worst Pruritus Numeric Rating Scale reduction of 4 or more from baseline were greater with tralokinumab, 150 mg (23.2%), and tralokinumab, 300 (25.0%), vs placebo (3.3%), and adjusted mean changes were greater in SCORing AD with tralokinumab, 150 mg (-27.5), and tralokinumab, 300 mg (-29.1), vs placebo (-9.5) and in Children's Dermatology Life Quality Index with tralokinumab, 150 mg (-6.1), and tralokinumab, 300 mg (-6.7), vs placebo (-4.1) at week 16. At week 52, tralokinumab efficacy was maintained without rescue in more than 50% of patients meeting primary end point(s) at week 16. In the open-label phase, IGA score of 0 or 1 and EASI 75 were achieved in 33.3% and 57.8%, respectively, at week 52. Tralokinumab was well tolerated, without frequency of conjunctivitis increasing through week 52.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, tralokinumab was efficacious and well tolerated, supporting its value for treating adolescents with moderate to severe AD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03526861.
Topics: Child; Humans; Male; Adolescent; Female; Dermatitis, Atopic; Treatment Outcome; Double-Blind Method; Severity of Illness Index; Eczema; Pruritus; Immunoglobulin A
PubMed: 37074705
DOI: 10.1001/jamadermatol.2023.0627 -
Gut Sep 2017To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis.
DATA SOURCES
We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC.
STUDY SELECTION
Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points.
DATA EXTRACTION AND SYNTHESIS
Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence.
OUTCOMES
Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δ) in the number of SBM/week and Δ CSBM/week.
RESULTS
Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δ in number of SBM/week.
CONCLUSIONS
Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δ in the number of SBM/week in CIC.
Topics: Azabicyclo Compounds; Benzofurans; Bisacodyl; Chronic Disease; Citrates; Constipation; Defecation; Drug Monitoring; Gastrointestinal Agents; Humans; Organometallic Compounds; Picolines; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27287486
DOI: 10.1136/gutjnl-2016-311835 -
JAMA Surgery Apr 2022The long-term benefits of off-pump ("beating heart") vs on-pump coronary artery bypass grafting (CABG) remain controversial. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The long-term benefits of off-pump ("beating heart") vs on-pump coronary artery bypass grafting (CABG) remain controversial.
OBJECTIVE
To evaluate the 10-year outcomes and costs of off-pump vs on-pump CABG in the Department of Veterans Affairs (VA) Randomized On/Off Bypass (ROOBY) trial.
DESIGN, SETTING, AND PARTICIPANTS
From February 27, 2002, to May 7, 2007, 2203 veterans in the ROOBY trial were randomly assigned to off-pump or on-pump CABG procedures at 18 participating VA medical centers. Per protocol, the veterans were observed for 10 years; the 10-year, post-CABG clinical outcomes and costs were assessed via centralized abstraction of electronic medical records combined with merges to VA and non-VA databases. With the use of an intention-to-treat approach, analyses were performed from May 7, 2017, to December 9, 2021.
INTERVENTIONS
On-pump and off-pump CABG procedures.
MAIN OUTCOMES AND MEASURES
The 10-year coprimary end points included all-cause death and a composite end point identifying patients who had died or had undergone subsequent revascularization (ie, percutaneous coronary intervention [PCI] or repeated CABG); these 2 end points were measured dichotomously and as time-to-event variables (ie, time to death and time to composite end points). Secondary 10-year end points included PCIs, repeated CABG procedures, changes in cardiac symptoms, and 2018-adjusted VA estimated costs. Changes from baseline to 10 years in post-CABG, clinically relevant cardiac symptoms were evaluated for New York Heart Association functional class, Canadian Cardiovascular Society angina class, and atrial fibrillation. Outcome differences were adjudicated by an end points committee. Given that pre-CABG risks were balanced, the protocol-driven primary and secondary hypotheses directly compared 10-year treatment-related effects.
RESULTS
A total of 1104 patients (1097 men [99.4%]; mean [SD] age, 63.0 [8.5] years) were enrolled in the off-pump group, and 1099 patients (1092 men [99.5%]; mean [SD] age, 62.5 [8.5] years) were enrolled in the on-pump group. The 10-year death rates were 34.2% (n = 378) for the off-pump group and 31.1% (n = 342) for the on-pump group (relative risk, 1.05; 95% CI, 0.99-1.11; P = .12). The median time to composite end point for the off-pump group (4.6 years; IQR, 1.4-7.5 years) was approximately 4.3 months shorter than that for the on-pump group (5.0 years; IQR, 1.8-7.9 years; P = .03). No significant 10-year treatment-related differences were documented for any other primary or secondary end points. After the removal of conversions, sensitivity analyses reconfirmed these findings.
CONCLUSIONS AND RELEVANCE
No off-pump CABG advantages were found for 10-year death or revascularization end points; the time to composite end point was lower in the off-pump group than in the on-pump group. For veterans, in the absence of on-pump contraindications, a case cannot be made for supplanting the traditional on-pump CABG technique with an off-pump approach.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01924442.
Topics: Canada; Coronary Artery Bypass; Coronary Artery Bypass, Off-Pump; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Treatment Outcome; Veterans
PubMed: 35171210
DOI: 10.1001/jamasurg.2021.7578 -
Journal of Clinical Oncology : Official... Aug 2021The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end...
PURPOSE
The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.
METHODS
We conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non-breast cancer deaths and new nonbreast primary cancers from the invasive disease-free survival end point.
RESULTS
Among 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.
CONCLUSION
We recommend an additional end point, invasive breast cancer-free survival, which includes all invasive disease-free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.
Topics: Breast Neoplasms; Endpoint Determination; Female; Humans; Research Design
PubMed: 34003702
DOI: 10.1200/JCO.20.03613 -
American Journal of Kidney Diseases :... Apr 2020Acute kidney injury (AKI) is a common outcome evaluated in clinical studies, often as a safety end point in a variety of cardiovascular, kidney disease, and other... (Review)
Review
Acute kidney injury (AKI) is a common outcome evaluated in clinical studies, often as a safety end point in a variety of cardiovascular, kidney disease, and other clinical trials. AKI end points that include modest increases in serum creatinine levels from baseline may not associate with patient-centered outcomes such as initiation of dialysis, sustained decline in kidney function, or death. Surprisingly, data from several randomized controlled trials have suggested that in certain settings, the development of AKI may be associated with favorable outcomes. AKI safety end points that are nonspecific and may not associate with patient-centered outcomes could result in beneficial therapies being inappropriately withheld or never developed for commercial use. We review several issues related to commonly used AKI definitions and suggest that future work in AKI use more patient-centered AKI end points such as major adverse kidney events at 30 days or other later time points.
Topics: Acute Kidney Injury; Creatinine; Endpoint Determination; Humans; Randomized Controlled Trials as Topic
PubMed: 32037098
DOI: 10.1053/j.ajkd.2019.11.010 -
Sensors (Basel, Switzerland) Aug 2022We propose a conceptually simple, general framework and end-to-end approach to point cloud completion, entitled PCA-Net. This approach differs from the existing methods...
We propose a conceptually simple, general framework and end-to-end approach to point cloud completion, entitled PCA-Net. This approach differs from the existing methods in that it does not require a "simple" network, such as multilayer perceptrons (MLPs), to generate a coarse point cloud and then a "complex" network, such as auto-encoders or transformers, to enhance local details. It can directly learn the mapping between missing and complete points, ensuring that the structure of the input missing point cloud remains unchanged while accurately predicting the complete points. This approach follows the minimalist design of U-Net. In the encoder, we encode the point clouds into point cloud blocks by iterative farthest point sampling (IFPS) and k-nearest neighbors and then extract the depth interaction features between the missing point cloud blocks by the attention mechanism. In the decoder, we introduce a new trilinear interpolation method to recover point cloud details, with the help of the coordinate space and feature space of low-resolution point clouds, and missing point cloud information. This paper also proposes a method to generate multi-view missing point cloud data using a 3D point cloud hidden point removal algorithm, so that each 3D point cloud model generates a missing point cloud through eight uniformly distributed camera poses. Experiments validate the effectiveness and superiority of PCA-Net in several challenging point cloud completion tasks, and PCA-Net also shows great versatility and robustness in real-world missing point cloud completion.
Topics: Algorithms; Cluster Analysis; Electric Power Supplies; Neural Networks, Computer; Research Design
PubMed: 36080900
DOI: 10.3390/s22176439 -
Science (New York, N.Y.) Jun 2023The barbed and pointed ends of the actin filament (F-actin) are the sites of growth and shrinkage and the targets of capping proteins that block subunit exchange,...
The barbed and pointed ends of the actin filament (F-actin) are the sites of growth and shrinkage and the targets of capping proteins that block subunit exchange, including CapZ at the barbed end and tropomodulin at the pointed end. We describe cryo-electron microscopy structures of the free and capped ends of F-actin. Terminal subunits at the free barbed end adopt a "flat" F-actin conformation. CapZ binds with minor changes to the barbed end but with major changes to itself. By contrast, subunits at the free pointed end adopt a "twisted" monomeric actin (G-actin) conformation. Tropomodulin binding forces the second subunit into an F-actin conformation. The structures reveal how the ends differ from the middle in F-actin and how these differences control subunit addition, dissociation, capping, and interactions with end-binding proteins.
Topics: Actin Cytoskeleton; Actins; Cryoelectron Microscopy; Tropomodulin; CapZ Actin Capping Protein; Protein Binding; Single Molecule Imaging; Protein Conformation
PubMed: 37228182
DOI: 10.1126/science.adg6812 -
Annals of Oncology : Official Journal... Jan 2010Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of... (Review)
Review
Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of drugs, combinations, and sequences to be tested. The choice of surrogate and true end points has become a critical issue and one that is currently the subject of much debate. Many recent randomized trials in solid tumor oncology have used progression-free survival (PFS) as the primary end point. PFS is an attractive end point because it is available earlier than overall survival (OS) and is not influenced by second-line treatments. PFS is now undergoing validation as a surrogate end point in various disease settings. The question of whether PFS can be considered an acceptable surrogate end point depends not only on formal validation studies but also on a standardized definition and unbiased ascertainment of disease progression in clinical trials. In advanced breast cancer, formal validation of PFS as a surrogate for OS has so far been unsuccessful. In advanced colorectal cancer, in contrast, current evidence indicates that PFS is a valid surrogate for OS after first-line treatment with chemotherapy. The other question is whether PFS sufficiently reflects clinical benefit to be considered a true end point in and of itself.
Topics: Biomarkers; Breast Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Epidemiologic Research Design; Female; Humans; Randomized Controlled Trials as Topic
PubMed: 19901012
DOI: 10.1093/annonc/mdp523