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Anesthesiology Apr 2024Propofol is an intravenous anesthetic associated with hypotension, respiratory depression, and injection-site pain. HSK3486 injectable emulsion (ciprofol) is a... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of the Efficacy of HSK3486 and Propofol for Induction of General Anesthesia in Adults: A Multicenter, Randomized, Double-blind, Controlled, Phase 3 Noninferiority Trial.
BACKGROUND
Propofol is an intravenous anesthetic associated with hypotension, respiratory depression, and injection-site pain. HSK3486 injectable emulsion (ciprofol) is a 2,6-disubstituted phenol derivative with fast onset and quick, stable recovery. Previous studies support HSK3486 as an effective, safe anesthetic with substantially less injection-site pain than propofol. The primary objective of this study was to investigate the noninferiority of HSK3486 compared with propofol in successful general anesthesia induction.
METHODS
Two hundred fifty-five participants were enrolled in HSK3486-304, a multicenter, randomized (2:1), double-blind, propofol-controlled, phase 3 study evaluating HSK3486 for general anesthesia induction in adults undergoing elective surgery with tracheal intubation. The primary endpoint was successful anesthesia induction, defined as 1 or less on the Modified Observer's Assessment of Alertness/Sedation scale. Key secondary endpoints were proportion of participants with injection-site pain on the Numerical Rating Scale of 1 or greater and a composite endpoint, including the proportion of participants successfully induced while maintaining the desired anesthetic depth and without substantial cardiac and respiratory events. Safety endpoints included adverse events, abnormal vital signs, and injection-site pain.
RESULTS
Two hundred fifty-one participants (HSK3486, n = 168; propofol, n = 83) were included in the analyses. General anesthesia was successfully induced in 97.0% versus 97.6% of participants with HSK3486 and propofol, respectively. The difference in success rate was -0.57% (95% CI, -5.4 to 4.2%); the noninferiority boundary of -8% was not crossed. Thirty participants (18.0%) had injection-site pain with HSK3486 versus 64 (77.1%) with propofol (P < 0.0001). Eighty-one participants (48.2%) with HSK3486 versus 42 (50.6%) with propofol (P = 0.8780) satisfied the composite endpoint. When injection-site pain was excluded, the incidence of treatment-emergent adverse events related to study drug was 17.9% for HSK3486 and 14.5% for propofol.
CONCLUSIONS
The study met its primary objective and endpoint, demonstrating noninferiority of HSK3486 compared with propofol in successful anesthetic induction. Substantially less injection-site pain was associated with HSK3486 than with propofol.
Topics: Adult; Humans; Propofol; Anesthetics, Intravenous; Pain; Anesthesia, General; Hypotension; Double-Blind Method
PubMed: 38150544
DOI: 10.1097/ALN.0000000000004886 -
Journal of Clinical Medicine Sep 2022Purpose: Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a bladder-related chronic inflammatory disease. Data indicate that stress enhances the excitability of...
Purpose: Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a bladder-related chronic inflammatory disease. Data indicate that stress enhances the excitability of bladder nociceptors through the stimulation of alpha1A-adrenoceptors. Stress is known to play a crucial role in BPS/IC patients. We aimed to assess the efficacy and safety of daily silodosin in refractory BPS/IC female patients and its correlation with stress coping. Materials and Methods: An open-label trial was conducted with 20 refractory BPS/IC patients. Evaluations occurred at baseline and the 8th and 12th weeks. Primary endpoint was bladder pain evaluated by visual analogue scale (VAS). Secondary endpoints included daily frequency, nocturia and maximum voided volume obtained from a 3-day bladder diary, the O’Leary−Sant Symptom Score, and two questions accessing stress coping. Patients initiated daily doses of 8 mg silodosin, which could be titrated to 16 mg. Median values with percentiles 25 and 75 (25; 75) were used. Wilcoxon signed-rank test was used for comparisons. A minimally important difference of 3 points for pain was established to define clinically relevant improvement. Results: Median age was 56 years. Median pain score decreased from 8.00 (6.00; 8.00) at baseline to 4.00 (2.00; 5.50) (p < 0.001), meaning that the primary endpoint was reached. Total urinary frequency decreased from 14.00 (13.00; 21.00) to 9.00 (7.50; 11.00) (p < 0.05), and all the other secondary endpoints also showed a statistically significant improvement. Eleven patients improved by ≥3 pain points in VAS, meaning that 65% of patients that ended the study protocol achieved clinical significant improvement or, in the full analysis set, that 55% of the 20 initial patients improved significantly. Fourteen (82%) decreased by ≥2 micturitions/day. Overall, the cohort’s stress coping was low. Conclusions: Silodosin can be an effective and well-tolerated treatment for refractory BPS/IC female patients.
PubMed: 36233527
DOI: 10.3390/jcm11195659 -
Animals : An Open Access Journal From... Dec 2019The purpose of this study was to assess the formation of chloramphenicol metabolites in primary turkey and rat hepatocyte cultures and human hepatoma (HepG2) cells and...
The purpose of this study was to assess the formation of chloramphenicol metabolites in primary turkey and rat hepatocyte cultures and human hepatoma (HepG2) cells and nonhepatic, Balb/c 3T3 fibroblasts. Additionally, the cytotoxicity of the drug was assessed through three biochemical endpoints: mitochondrial and lysosomal activity and cellular membrane integrity after 24 and 48 h exposure. The two metabolites of the drug, chloramphenicol glucuronide and nitroso-chloramphenicol, were detected to the greatest extent in both primary hepatocyte cultures by liquid chromatography-tandem mass spectrometry. Toxic nitroso-chloramphenicol was the main metabolite in the primary turkey hepatocyte cultures, but it was not in the primary rat hepatocyte cultures. The most affected endpoint in turkey and rat hepatocyte cultures was the disintegration of the cellular membrane, but in the cell lines, mitochondrial and lysosomal activities underwent the greatest change. The primary hepatocyte cultures represent valuable tools with which to study the species differences in the biotransformation and toxicity of drugs. To the best of our knowledge, this is the first report of differences in chloramphenicol metabolism in primary turkey and rat hepatocyte cultures.
PubMed: 31877810
DOI: 10.3390/ani10010030 -
Heliyon May 2023Infection with SARs-COV-2 results in COVID-19 disease. Between March 2020 and August 2021, 468 COVID-19 patients confirmed by PCR or antigen test, in Yepes, Spain,...
Infection with SARs-COV-2 results in COVID-19 disease. Between March 2020 and August 2021, 468 COVID-19 patients confirmed by PCR or antigen test, in Yepes, Spain, received early treatment with antihistamines, adding azithromycin in selected cases. The primary endpoint is the hospitalization rate of COVID-19 patients, and the secondary endpoints are ICU admission and mortality rates. All endpoints are compared with the official Spanish rates during the time period of the study. There were 20 hospital admissions (hospitalization rate 4,3%), 5 ICU admissions (ICU admission rate 1,1%) and 3 deaths (fatality rate of 0,6%). No patients in the study required follow up treatment, which suggest they did not develop long COVID. Results from this retrospective trail indicate that early treatment of SARS-COV-2 positive patients with antihistamines may reduce the odds of hospitalization (OR: 0.490, CI: 0.313-0.767, p-value: 0.001). Randomized controlled clinical trials are needed to further evaluate the effects of early antihistamine treatment of SARS-CoV-2 patients to prevent hospitalization, ICU admission, mortality and long-covid.
PubMed: 37128299
DOI: 10.1016/j.heliyon.2023.e15772 -
ACR Open Rheumatology Jul 2022Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021;384:599-609.
JOURNAL CLUB
Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021;384:599-609.
OBJECTIVE
The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
METHODS
In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary endpoint was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary endpoint was sustained remission, defined as remission at both weeks 26 and 52. Both endpoints were tested for noninferiority (by a margin of 20 percentage points) and for superiority.
RESULTS
A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary endpoint) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P < 0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary endpoint) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P < 0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone.
CONCLUSION
In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.). https://pubmed.ncbi.nlm.nih.gov/33596356/ ANCA-associated vasculitis (AAV) is a chronic autoimmune disease characterized by progressive pauci-immune glomerulonephritis and inflammation of the respiratory tract traditionally requiring treatment with corticosteroids. The ADVOCATE trial was a phase III randomized double-blind placebo-controlled clinical trial to investigate whether avacopan, a C5a receptor inhibitor involved in blocking complement activation, could replace steroids in induction therapy for AAV in addition to standard-of-care therapy via a noninferiority trial design. The ADVOCATE trial met its primary endpoint of clinical remission at week 26 (3.4% difference between treatment and placebo; 95% CI: -6.0 to 12.8%; P < 0.001 for noninferiority) and at week 52 (12.5% difference; 95% CI: 2.6% to 22.3%; P = 0.007 for superiority). Strengths of this study include its international and multicenter involvement, rigorous study design and analysis, and minimal loss to follow-up. Potential weaknesses of this study include the lack of rituximab maintenance as part of standard-of-care treatment beyond week 4 of induction therapy and complete wean off prednisone by week 21, much faster than steroid weans in prior trials (including PEXIVAS), which may somewhat limit our interpretation of the noninferiority of avacopan to prednisone. Overall, the ADVOCATE trial yielded thought-provoking clinical implications that may revolutionize AAV treatment moving forward, including less reliance on corticosteroids to achieve clinical remission in AAV.
PubMed: 35167187
DOI: 10.1002/acr2.11412 -
Frontiers in Oncology 2020Basal cell carcinoma (BCC) located on the genitalia is rare; data on the clinicopathologic features and survival outcomes are only available through case reports and...
INTRODUCTION
Basal cell carcinoma (BCC) located on the genitalia is rare; data on the clinicopathologic features and survival outcomes are only available through case reports and small case series studies.
PURPOSE
This study aimed to explore the epidemiology and identify the prognostic factors of genital BCCs.
METHODS
We queried the 18 registries of the Surveillance, Epidemiology, and End Results database for patients with primary BCCs of the genital skin from 2000 through 2017. The primary endpoint was overall survival (OS) and disease specific survival (DSS). Kaplan-Meier survival analysis was conducted to assess the impact of clinicopathological variables on OS and DSS. Multivariate Cox proportional hazards model was performed to evaluate risk factors for OS.
RESULTS
A total of 1,607 cases of genital BCCs were identified. The cohort was composed of 1,352 women (84.1%) and 255 men (15.9%). The median (P25, P75) age of the entire cohort was 73(63-82)years. White patients accounted for 87.2% of the cases. For women and men, the most common site of involvement was the labia majora (89.6%) and scrotum (74.5%), respectively. The majority of patients with genital BCC had localized disease (75.5%). Kaplan-Meier survival analysis showed that female genital BCCs experienced better DSS than men (209.1 months vs 194.8 months); for men, BCCs located on the scrotum had better DSS and OS than those on the penis (P < 0.05 for both endpoints). All patients with distant disease died of disease-specific death, and the average survival time was 8.2 months. Multivariate analysis revealed that age, primary site, and stage were independent determinants of OS for men, while tumor size, histologic subtype, and race were not. For women, factors associated with worse OS included increasing age, tumor size more than 2 cm, and distant disease; factors associated with a decreased risk included "other" and "unknown" races.
CONCLUSION
The prognosis of genital BCCs is excellent, while the survival of distant disease is very poor. Despite similar clinicopathologic features and overall survival outcomes, men and women should be treated as two different entities when making survival predictions.
PubMed: 33585236
DOI: 10.3389/fonc.2020.613533 -
Otology & Neurotology : Official... Jul 2023To determine the efficacy of intratympanic OTO-104 for the treatment of Ménière's disease. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To determine the efficacy of intratympanic OTO-104 for the treatment of Ménière's disease.
STUDY DESIGNS
Three randomized, double-blind, placebo-controlled, multicenter studies of OTO-104 in patients with Ménière's disease.
SETTING
The United States and throughout Europe.
PATIENTS
Individuals with Ménière's disease aged 18 to 85 years.
INTERVENTIONS
All three studies were conducted according to a similar protocol, whereby after a 1-month lead-in period, eligible patients received a single intratympanic injection of either 12 mg OTO-104 (otic formulation of dexamethasone in thermosensitive poloxamer) or placebo (1:1) and were observed for 3 months.
MAIN OUTCOME MEASURES
The primary efficacy endpoint was measured by the number of definitive vertigo days (DVDs) at month 3. Secondary objective was OTO-104 safety and tolerability including adverse events, audiometry, tympanometry, and otoscopic examinations.
RESULTS
Although OTO-104 demonstrated numerically greater reductions in DVD compared with placebo across all three studies, statistical significance versus placebo (primary efficacy endpoint) was only achieved in one study, the AVERTS-2 study (n = 174, p = 0.029). Secondary vertigo efficacy endpoints were statistically significant at month 3 in that study including vertigo severity, the effect of vertigo on daily activity (days at home sick or bedridden), and vertigo frequency. In the AVERTS-1 study, which did not meet the primary endpoint, a subgroup analysis of the 115 patients (69.7% of study population) who did not previously receive intratympanic steroid injections demonstrated that OTO-104 patients had significantly lower mean DVD at month 3 than patients receiving placebo (1.9 for OTO-104 versus 3.0 for placebo; p = 0.045). Importantly, a significant placebo response was observed across studies in Ménière's disease patients. OTO-104 and the intratympanic injection procedure were well tolerated.
CONCLUSIONS
In all three high-quality, randomized, double-blind, placebo-controlled, multicenter studies, a single intratympanic injection of 12 mg OTO-104 demonstrated numerically greater reductions in vertigo versus placebo in patients with Ménière's disease, but statistical separation from placebo was demonstrated in only one of the studies. OTO-104 was safe and well tolerated.(Otonomy, Inc. funded; NCT02717442, NCT02612337, NCT03664674).
Topics: Humans; Meniere Disease; Vertigo; Injections; Injection, Intratympanic; Double-Blind Method; Treatment Outcome; Gentamicins
PubMed: 37185596
DOI: 10.1097/MAO.0000000000003886 -
Orphanet Journal of Rare Diseases Apr 2022The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating...
BACKGROUND
The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases.
RESULTS
Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure-response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed.
CONCLUSIONS
Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure-response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.
Topics: Biological Products; Drug Approval; Drug Development; Humans; Rare Diseases; Research Design; United States; United States Food and Drug Administration
PubMed: 35382851
DOI: 10.1186/s13023-022-02298-6 -
BMC Psychiatry Sep 2023Sleep is necessary for healthy development and mental wellbeing. Despite this, many children do not get the recommended duration of sleep each night, and many experience...
BACKGROUND
Sleep is necessary for healthy development and mental wellbeing. Despite this, many children do not get the recommended duration of sleep each night, and many experience sleep problems. Although treatable, existing interventions for sleep disturbance are time-consuming, burdensome for families, and focus on providing behavioural strategies to parents rather than upskilling children directly. To address this gap, we modified Sleep Ninja®, an evidence-based cognitive behavioural therapy for insomnia (CBT-I) smartphone app for adolescent sleep disturbance, to be appropriate for 10 to 12 year olds. Here, we describe the protocol for a randomised controlled trial to evaluate the effect of Sleep Ninja on insomnia and other outcomes, including depression, anxiety, sleep quality, and daytime sleepiness, and explore effects on the emergence of Major Depressive Disorder (MDD), compared to an active control group.
METHODS
We aim to recruit 214 children aged 10 to 12 years old experiencing disturbed sleep. Participants will be screened for inclusion, complete the baseline assessment, and then be randomly allocated to receive Sleep Ninja, or digital psychoeducation flyers (active control) for 6-weeks. The primary outcome, insomnia symptoms, along with depression, anxiety, sleep quality, and daytime sleepiness will be assessed at 6-weeks (primary endpoint), 3-months, and 9-months post-baseline (secondary and tertiary endpoints, respectively). A mixed model repeated measures analytic approach will be used to conduct intention-to-treat analyses to determine whether reductions in insomnia and secondary outcomes are greater for those receiving Sleep Ninja relative to the control condition at the primary and secondary endpoints. The difference in relative risk for MDD onset will be explored at 9-months and compared between conditions.
DISCUSSION
This is the first clinical trial examining the effects of a CBT-I smartphone app in children experiencing sleep disturbance. Results will provide empirical evidence about the effects of Sleep Ninja on insomnia and other mental health outcomes.
TRIAL REGISTRATION
Australian New Zealand Clinical Trials Registry (ACTRN12623000587606).
UNIVERSAL TRIAL NUMBER
U1111-1294-4167.
Topics: Adolescent; Child; Humans; Sleep Initiation and Maintenance Disorders; Depressive Disorder, Major; Mobile Applications; Smartphone; Australia; Sleep; Cognitive Behavioral Therapy; Disorders of Excessive Somnolence; Randomized Controlled Trials as Topic
PubMed: 37730577
DOI: 10.1186/s12888-023-05185-x -
Clinical Lymphoma, Myeloma & Leukemia Apr 2023Development of myelofibrosis (MF) therapeutics has reached fruition as the transformative impact of JAK2 inhibitors in the MPN landscape is complemented/expanded by a... (Review)
Review
Development of myelofibrosis (MF) therapeutics has reached fruition as the transformative impact of JAK2 inhibitors in the MPN landscape is complemented/expanded by a profusion of novel monotherapies and rational combinations in the frontline and second line settings. Agents in advanced clinical development span various mechanisms of action (eg, epigenetic or apoptotic regulation), may address urgent unmet clinical needs (cytopenias), increase the depth/duration of spleen and symptom responses elicited by ruxolitinib, improve other aspects of the disease besides splenomegaly/constitutional symptoms (eg, resistance to ruxolitinib, bone marrow fibrosis or disease course), provide personalized strategies, and extend overall survival (OS). Ruxolitinib had a dramatic impact on the quality of life and OS of MF patients. Recently, pacritinib received regulatory approval for severely thrombocytopenic MF patients. Momelotinib is advantageously poised among JAK inhibitors given its differentiated mode of action (suppression of hepcidin expression). Momelotinib demonstrated significant improvements in anemia measures, spleen responses, and MF-associated symptoms in MF patients with anemia; and will likely receive regulatory approval in 2023. An array of other novel agents combined with ruxolitinib, such as pelabresib, navitoclax, parsaclisib, or as monotherapies (navtemadlin) are evaluated in pivotal phase 3 trials. Imetelstat (telomerase inhibitor) is currently evaluated in the second line setting; OS was set as the primary endpoint, marking an unprecedented goal in MF trials, wherein SVR35 and TSS50 at 24 weeks have been typical endpoints heretofore. Transfusion independence may be considered another clinically meaningful endpoint in MF trials given its correlation with OS. Overall, therapeutics are at the cusp of an exponential expansion and advancements that will likely lead to the golden era in treatment of MF.
Topics: Humans; Primary Myelofibrosis; Janus Kinase 2; Quality of Life; Protein Kinase Inhibitors
PubMed: 36797153
DOI: 10.1016/j.clml.2022.12.014