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The Journal of Clinical Endocrinology... Jul 2023Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause. (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause.
OBJECTIVE
We aimed to assess efficacy/safety of fezolinetant for treatment of moderate to severe VMS associated with menopause.
METHODS
In this double-blind, placebo-controlled, 12-week phase 3 trial with a 40-week active treatment extension (NCT04003142; SKYLIGHT 2), women aged 40 to 65 years with minimum average 7 moderate to severe VMS/day were randomized to 12 weeks of once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Completers were rerandomized to fezolinetant 30/45 mg for 40 additional weeks. Coprimary efficacy endpoints were mean daily change from baseline to week 4 (W4) and W12 in VMS frequency and severity. Safety was also assessed.
RESULTS
Both fezolinetant doses statistically significantly reduced VMS frequency/severity at W4 and W12 vs placebo. For VMS frequency, W4 least squares mean (SE) reduction vs placebo: fezolinetant 30 mg, -1.82 (0.46; P < .001); 45 mg, -2.55 (0.46; P < .001); W12: 30 mg, -1.86 (0.55; P < .001); 45 mg, -2.53 (0.55; P < .001). For VMS severity, W4: 30 mg, -0.15 (0.06; P < .05); 45 mg, -0.29 (0.06; P < .001); W12: 30 mg, -0.16 (0.08; P < .05); 45 mg, -0.29 (0.08; P < .001). Improvement in VMS frequency and severity was observed by W1 and maintained through W52. Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively.
CONCLUSION
Daily fezolinetant 30 and 45 mg were efficacious and well tolerated for treating moderate to severe VMS associated with menopause.
Topics: Female; Humans; Hot Flashes; Treatment Outcome; Menopause; Double-Blind Method
PubMed: 36734148
DOI: 10.1210/clinem/dgad058 -
Kidney International Jan 2024Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan... (Randomized Controlled Trial)
Randomized Controlled Trial
Targeting the alternative complement pathway is an attractive therapeutic strategy given its role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Iptacopan (LNP023) is an oral, proximal alternative complement inhibitor that specifically binds to Factor B. Our randomized, double-blind, parallel-group adaptive Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within previous three years) with estimated glomerular filtration rates of 30 mL/min/1.73 m and over and urine protein 0.75 g/24 hours and over on stable doses of renin angiotensin system inhibitors. Patients were randomized to four iptacopan doses (10, 50, 100, or 200 mg bid) or placebo for either a three-month (Part 1; 46 patients) or a six-month (Part 2; 66 patients) treatment period. The primary analysis evaluated the dose-response relationship of iptacopan versus placebo on 24-hour urine protein-to-creatinine ratio (UPCR) at three months. Other efficacy, safety and biomarker parameters were assessed. Baseline characteristics were generally well-balanced across treatment arms. There was a statistically significant dose-response effect, with 23% reduction in UPCR achieved with iptacopan 200 mg bid (80% confidence interval 8-34%) at three months. UPCR decreased further through six months in iptacopan 100 and 200 mg arms (from a mean of 1.3 g/g at baseline to 0.8 g/g at six months in the 200 mg arm). A sustained reduction in complement biomarker levels including plasma Bb, serum Wieslab, and urinary C5b-9 was observed. Iptacopan was well-tolerated, with no reports of deaths, treatment-related serious adverse events or bacterial infections, and led to strong inhibition of alternative complement pathway activity and persistent proteinuria reduction in patients with IgAN. Thus, our findings support further evaluation of iptacopan in the ongoing Phase 3 trial (APPLAUSE-IgAN; NCT04578834).
Topics: Humans; Glomerulonephritis, IGA; Treatment Outcome; Complement Pathway, Alternative; Immunologic Factors; Biomarkers; Double-Blind Method
PubMed: 37914086
DOI: 10.1016/j.kint.2023.09.027 -
Nature Medicine Nov 2023Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled... (Randomized Controlled Trial)
Randomized Controlled Trial
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (-11.1%, -12.6%), apoB (-15.6%, -18.0%), triglycerides (-15.4%, -20.4%), 16-week hepatic fat (-34.9%, -38.6%), (P < 0.0001) and liver stiffness (-1.02, -1.70) and 52-week hepatic fat (-28.8, -33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479 ).
Topics: Adult; Humans; Apolipoproteins B; Cholesterol, LDL; Double-Blind Method; Liver; Non-alcoholic Fatty Liver Disease; Treatment Outcome; Triglycerides
PubMed: 37845512
DOI: 10.1038/s41591-023-02603-1 -
Medicine Oct 2023The coronavirus disease-2019 (COVID-19) pandemic has resulted in a surge in stress, anxiety, and depression worldwide. Ashwagandha, an ayurvedic adaptogen has been... (Randomized Controlled Trial)
Randomized Controlled Trial
A standardized Ashwagandha root extract alleviates stress, anxiety, and improves quality of life in healthy adults by modulating stress hormones: Results from a randomized, double-blind, placebo-controlled study.
BACKGROUND
The coronavirus disease-2019 (COVID-19) pandemic has resulted in a surge in stress, anxiety, and depression worldwide. Ashwagandha, an ayurvedic adaptogen has been traditionally used to manage stress, anxiety, and general well-being.
OBJECTIVE
We assessed the effect of Ashwagandha root extract (ARE-500 mg) standardized for 2.5% withanolides as per USP protocol with piperine (5 mg of 95% piperine) once daily for 60 days (12.5 mg withanolides/day) to alleviate stress and anxiety in healthy individuals with mild to moderate symptoms.
METHODS
A randomized, double-blind, placebo-controlled study was conducted for 60 days using ARE (n = 27) and placebo (n = 27) once daily at night at Narayana Institute of Cardiac Sciences, Bangalore, and Vijaya Super Specialty Hospital, Nellore, in India. The objectives of this study were to assess an improvement in perceived stress scale (PSS), generalized anxiety disorder (GAD-7), quality of life (QOL), cognitive scores in the Cambridge Neuropsychological Test Automated Battery (CANTAB), changes in salivary cortisol, urinary serotonin, dopamine, serum levels of nitric oxide (NO), glutathione (GSH) and malondialdehyde (MDA) from baseline to end of the study. Safety was evaluated by laboratory parameters, and by monitoring any incidence of adverse events.
RESULTS
54 individuals were randomized and 50 of them completed the study. The PSS, GAD-7, and QOL scores improved significantly in all the participants taking ARE compared to the placebo. The CANTAB analysis revealed a significant improvement in multitasking, concentration, and decision taking time in ARE compared to placebo. ARE was also associated with a greater reduction in the morning salivary cortisol and an increase in urinary serotonin compared to placebo. Serum levels of NO, GSH, and MDA were not significantly different. Biochemical and hematological parameters remained in the normal range in all participants and ARE was well tolerated during the study.
CONCLUSION
The results of the study suggest that ARE with 2.5% withanolides can effectively improve stress and anxiety by reducing cortisol and increasing serotonin in healthy individuals with mild to moderate symptoms.
Topics: Humans; Adult; Quality of Life; Hydrocortisone; Serotonin; Withanolides; COVID-19; India; Anxiety Disorders; Anxiety; Double-Blind Method
PubMed: 37832082
DOI: 10.1097/MD.0000000000035521 -
BMC Public Health Dec 2023Randomized trials have shown that vitamin C shortens the duration of common colds. Some trials reported greater effects on severe cold symptoms compared with mild... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Randomized trials have shown that vitamin C shortens the duration of common colds. Some trials reported greater effects on severe cold symptoms compared with mild symptoms. This review systematically compares the effects of vitamin C on severe and mild common cold symptoms.
METHODS
We included all placebo-controlled trials of orally administered vitamin C in doses of at least 1 g/day for the common cold for people in good health at baseline. The analysis was restricted to trials which reported both the total duration of the common cold, and the severity of the common cold measured using severity scales, the duration of more severe stages of the cold, or proxies for severe colds such as days indoors. Findings were pooled using the inverse variance, fixed effect options of the metacont function of the R package meta to calculate the ratio of means estimate.
RESULTS
Fifteen comparisons from 10 trials which reported both mild and severe symptoms were identified. All trials were randomized and double-blind. Compared to placebo, vitamin C significantly decreased the severity of the common cold by 15% (95% CI 9-21%). The direct comparison of the effect of vitamin C on mild and severe symptoms was limited to five comparisons which found that vitamin C had a significant benefit on the duration of severe symptoms. In this subset, there was a significant difference in the size of the effect of vitamin C on the overall duration of colds versus the duration of severe colds (P = 0.002), and vitamin C had no significant effect on the duration of mild symptoms.
CONCLUSIONS
The common cold is the leading cause of acute morbidity and a major cause of absenteeism from work and school. However, absenteeism is dependent on the severity of symptoms. The finding that vitamin C may have a greater effect on more severe measures of the common cold is therefore important. Further research on the therapeutic effects of vitamin C on the common cold should measure outcomes of differing levels of severity.
Topics: Humans; Common Cold; Ascorbic Acid; Vitamins; Double-Blind Method; Absenteeism; Randomized Controlled Trials as Topic
PubMed: 38082300
DOI: 10.1186/s12889-023-17229-8 -
Movement Disorders : Official Journal... Aug 2023Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD.
OBJECTIVES
To investigate the safety and tolerability of high-dose UDCA in PD and determine midbrain target engagement.
METHODS
The UP (UDCA in PD) study was a phase II, randomized, double-blind, placebo-controlled trial of UDCA (30 mg/kg daily, 2:1 randomization UDCA vs. placebo) in 30 participants with PD for 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included 31-phosphorus magnetic resonance spectroscopy ( P-MRS) to explore target engagement of UDCA in PD midbrain and assessment of motor progression, applying both the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) and objective, motion sensor-based quantification of gait impairment.
RESULTS
UDCA was safe and well tolerated, and only mild transient gastrointestinal adverse events were more frequent in the UDCA treatment group. Midbrain P-MRS demonstrated an increase in both Gibbs free energy and inorganic phosphate levels in the UDCA treatment group compared to placebo, reflecting improved ATP hydrolysis. Sensor-based gait analysis indicated a possible improvement of cadence (steps per minute) and other gait parameters in the UDCA group compared to placebo. In contrast, subjective assessment applying the MDS-UPDRS-III failed to detect a difference between treatment groups.
CONCLUSIONS
High-dose UDCA is safe and well tolerated in early PD. Larger trials are needed to further evaluate the disease-modifying effect of UDCA in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Ursodeoxycholic Acid; Double-Blind Method
PubMed: 37246815
DOI: 10.1002/mds.29450 -
Virology Journal Nov 2023In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence.
OBJECTIVES
To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19.
METHODS
We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms.
RESULTS
The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported.
INTERPRETATION
LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .
Topics: Adult; Humans; COVID-19; Double-Blind Method; Drugs, Chinese Herbal; Treatment Outcome
PubMed: 38017515
DOI: 10.1186/s12985-023-02144-6 -
BMC Medicine Nov 2023Creatine is an organic compound that facilitates the recycling of energy-providing adenosine triphosphate (ATP) in muscle and brain tissue. It is a safe, well-studied... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Creatine is an organic compound that facilitates the recycling of energy-providing adenosine triphosphate (ATP) in muscle and brain tissue. It is a safe, well-studied supplement for strength training. Previous studies have shown that supplementation increases brain creatine levels, which might increase cognitive performance. The results of studies that have tested cognitive performance differ greatly, possibly due to different populations, supplementation regimens, and cognitive tasks. This is the largest study on the effect of creatine supplementation on cognitive performance to date.
METHODS
Our trial was preregistered, cross-over, double-blind, placebo-controlled, and randomised, with daily supplementation of 5 g for 6 weeks each. We tested participants on Raven's Advanced Progressive Matrices (RAPM) and on the Backward Digit Span (BDS). In addition, we included eight exploratory cognitive tests. About half of our 123 participants were vegetarians and half were omnivores.
RESULTS
Bayesian evidence supported a small beneficial effect of creatine. The creatine effect bordered significance for BDS (p = 0.064, η = 0.029) but not RAPM (p = 0.327, η = 0.008). There was no indication that creatine improved the performance of our exploratory cognitive tasks. Side effects were reported significantly more often for creatine than for placebo supplementation (p = 0.002, RR = 4.25). Vegetarians did not benefit more from creatine than omnivores.
CONCLUSIONS
Our study, in combination with the literature, implies that creatine might have a small beneficial effect. Larger studies are needed to confirm or rule out this effect. Given the safety and broad availability of creatine, this is well worth investigating; a small effect could have large benefits when scaled over time and over many people.
TRIAL REGISTRATION
The trial was prospectively registered (drks.de identifier: DRKS00017250, https://osf.io/xpwkc/ ).
Topics: Humans; Creatine; Bayes Theorem; Dietary Supplements; Brain; Double-Blind Method; Cognition
PubMed: 37968687
DOI: 10.1186/s12916-023-03146-5 -
Journal of Psychopharmacology (Oxford,... Nov 2023Stress is a state of homeostasis in the body being challenged, resulting in a systemic response. It has become more prevalent in recent years and affects mental and... (Randomized Controlled Trial)
Randomized Controlled Trial
Exploring the efficacy and safety of a novel standardized ashwagandha () root extract (Witholytin®) in adults experiencing high stress and fatigue in a randomized, double-blind, placebo-controlled trial.
BACKGROUND
Stress is a state of homeostasis in the body being challenged, resulting in a systemic response. It has become more prevalent in recent years and affects mental and physical health.
AIMS
Evaluate the effects of ashwagandha on stress, fatigue, and sex hormones in overweight or mildly obese men and women with self-reported stress and fatigue.
METHODS
Two-arm, parallel-group, 12-week, randomized, double-blind, placebo-controlled trial on overweight or mildly obese men and women aged 40-75 years, supplementing with 200 mg of an ashwagandha root extract (Witholytin®) twice daily.
RESULTS/OUTCOMES
Supplementation with ashwagandha was associated with a significant reduction in stress levels based on the Perceived Stress Scale (primary outcome); however, the improvements were not significantly different to the placebo group ( = 0.867). Based on the Chalder Fatigue Scale, there was a statistically significant reduction in fatigue symptoms in the ashwagandha group compared to the placebo group ( = 0.016), and participants taking ashwagandha also experienced a significant increase in heart rate variability ( = 0.003). However, there were no significant between-group differences in other self-report outcome measures. In the men taking ashwagandha, there was a significant increase in the blood concentrations of free testosterone ( = 0.048) and luteinizing hormone ( = 0.002) compared to the placebo group.
CONCLUSIONS/INTERPRETATION
The results of this study suggest that in overweight middle-to-older age adults experiencing high stress and fatigue, compared to the placebo, ashwagandha did not have a significantly greater impact on perceived stress levels. However, based on secondary outcome measures, it may have anti-fatigue effects. This may be via its impact on the autonomic nervous system. However, further research is required to expand on these current findings.
Topics: Male; Humans; Adult; Female; Withania; Overweight; Plant Extracts; Double-Blind Method; Obesity; Fatigue
PubMed: 37740662
DOI: 10.1177/02698811231200023 -
Nature Medicine Nov 2023Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving β cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004-0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41 .
Topics: Child; Adolescent; Humans; Diabetes Mellitus, Type 1; Ribavirin; C-Peptide; Double-Blind Method; Antiviral Agents
PubMed: 37789144
DOI: 10.1038/s41591-023-02576-1