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BackgroundMethodsResultsConclusionsL-theanine is a non-protein-forming amino acid found in tea. Limited evidence suggests that it improves selective attention. Sleep deprivation impairs attention and psychomotor reactions, affecting automobile driving. We aimed to determine whether L-theanine improves neurobehavioral measures of visual attention in acutely sleep-deprived healthy adults in a traffic-scene-based attention task.In a double-blind, placebo-controlled, counterbalanced, two-way crossover study, we compared the effects of a 200-mg dose of L-theanine with a placebo (150 ml of distilled water) on a computerised, traffic-scene-based visual recognition reaction task in 24 healthy volunteers (age 20–25 years; 13 males) sleep-deprived overnight. The participants made speeded button-presses to imminent accident scenes (i.e. hits), while ignoring safe scenes. They were tested pre-dose and 45 min post-dose, each treatment administered one week apart.Hit rates were more than 90% in all sessions, and were similar in two treatments, pre- vs post-dose. L-theanine significantly reduced false alarms (i.e. responses to safe scenes) (p = 0.014) and increased A′ (i.e. target-distractor discriminability) (p = 0.009), whereas placebo did not (p > 0.05). L-theanine reduced hit reaction time by 38.65 ms (p = 0.007), and placebo by 19.08 ms (p = 0.016), however reaction time changes from baseline were not significantly different between treatments (p > 0.05).L-theanine in high doses appears to improve selective visual attention by concurrently improving information processing speed and target-distractor discriminability in acutely sleep-deprived individuals. This is consistent with previous functional neuroimaging findings, where L-theanine suppressed distractor-processing and default-mode-network activity in visual selective attention tasks. [ABSTRACT FROM AUTHOR]

Antipsychotic drug efficacy may vary in placebo-controlled and active-controlled trials. The study aims to investigate the performance of antipsychotics in these two different study designs using single-arm meta-analysis. We included randomized controlled trials (RCTs) comparing second-generation antipsychotics with placebo or other antipsychotics from our previous systematic reviews and updated the results with the search on Cochrane Schizophrenia Group register until March 06, 2022. The outcomes were the differences in the change of overall, positive and negative symptoms of schizophrenia, and the difference in study discontinuation between placebo-controlled and head-to-head trials. Random-effects single-arm meta-analysis and subgroup test were conducted to examine the differences in each outcome. A total of 208 RCTs (n = 42,159) were included in the analysis. Of these, 85 trials with 17,056 participants were placebo-controlled, while the remaining were head-to-head trials. Antipsychotics in head-to-head trials demonstrated a significantly greater improvement in overall symptoms (MC −23.58; 95 % CI −25.33, −21.83) compared to antipsychotics in placebo-controlled trials (MC −16.74; 95 % CI −17.80, −15.69; p < 0.0001). Similar findings were observed for positive symptoms, negative symptoms, study discontinuation and sensitivity analyses. Notably, when assessing antipsychotics individually, the same antipsychotic consistently demonstrated superior performance in head-to-head trials compared to placebo-controlled trials. In conclusion, antipsychotics in head-to-head trials presented a considerable efficacy superiority compared to those in placebo-controlled trials. Moreover, the efficacy of the same antipsychotics varied depending on the study design. Future trials should carefully consider the methodology and employ strategies to mitigate the potential for overestimation or underestimation of treatment efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Balloon Eustachian tuboplasty (BET) is used to treat obstructive Eustachian tube dysfunction (OETD) and recurrent otitis media with effusion (OME). However, there are no indisputable evidence of its efficacy. Here, we present a multicenter, double‐blinded, randomized, placebo‐controlled trial (MDRCT) design to evaluate the efficacy of BET, and the results of a pilot trial with 3‐ and 12‐months' follow‐up. Material and Methods: This was a prospective MDRCT. For a pilot study, OETD (n = 10) and OME (n = 5) patients were recruited and followed. Detailed inclusion and exclusion criteria were used. Participants were randomized at beginning of the operation to active or sham surgery. All procedures were performed under local anesthesia. Controls were performed in double‐blinded manner (both patient and physician), at 3 and 12 months after the procedure. Results: Altogether, 20 ears were treated and followed for 12 months, including 14 active BETs and 6 sham surgeries. Both the active and sham surgery were performed under local anesthesia without problems or deviations from the protocol. There were no differences in the preoperative symptoms (ETDQ‐7) or objective measures (tympanometry, Valsalva and Toynbee maneuvers, tubomanometry, Eustachian tube score) between active and sham surgery arms. During follow‐up, we noticed largely similar reduction in subjective symptoms and improvement in Eustachian tube score both in active and sham surgery arms. Conclusions: The pilot study demonstrates that our MDRCT protocol is feasible, and that blinded RCTs are dearly needed to objectively measure the efficacy of BET. Level of Evidence: 2 Laryngoscope, 134:1874–1881, 2024 [ABSTRACT FROM AUTHOR]

Placebo-controlled, acute treatment trials in schizophrenia enroll acutely symptomatic persons, randomize them to receive placebo or antipsychotic medication for several weeks, and evaluate whether symptoms improve. These trials can have scientific benefits, especially when they test drugs with novel mechanisms of action. However, the use of placebo is ethically problematic inasmuch as standard treatment is withheld and participants are subjected to prolonged psychotic symptoms and associated risks. We propose that both deontological (duty-based) and utilitarian analyses are relevant, that it may be impossible to satisfy the ideals of both frameworks, and that researchers who conduct these trials will unavoidably encounter ethical tension and criticism even when they give careful attention to ethical aspects of study design. [ABSTRACT FROM AUTHOR]

Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, μ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, μ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888 [ABSTRACT FROM AUTHOR]

Background: L-theanine is a non-protein-forming amino acid found in tea. Previous research shows high doses (100–400 mg) of L-theanine enhances attention, mainly by reducing mind wandering and distracter processing. We hypothesized that these indirect mechanisms could significantly improve the performance of low-level attentional tasks, whereas the relative contribution could be less in complex attentional tasks that require active, higher-order processing of target stimuli. Methods: To test this hypothesis, we conducted a double-blind, placebo-controlled, counterbalanced, four-way crossover study in 32 healthy young adults, where we compared the effects of three doses of L-theanine (100, 200 and 400 mg) with a placebo (distilled water), administered before and 50 min after dosing, on three attentional tasks from the Cambridge Neuropsychological Test Automated Battery [viz. Reaction Time (RTI)–visuomotor speed, Rapid Visual Information Processing (RVP)–sustained attention, and Stop Signal Task (SST)–inhibitory control]. Results were analyzed in dose × time repeated measures ANOVA models, with subsequent pairwise comparisons. Results: Active doses significantly improved reaction times in the RTI (100–200 mg) and RVP (200–400 mg) tasks from baseline (p < 0.05), but once controlled for the change-from-baseline caused by placebo, only the RTI simple reaction times showed significant improvements, following 100 mg (Δ = 16.3 ms, p = 0.009) and 200 mg (Δ = 16.9 ms, p = 0.009) of L-theanine. Conclusions: Consistent with our hypothesis, these findings suggest that L-theanine significantly improves attention in simple visuomotor tasks, but not in more complex sustained attention tasks, or executive control tasks that require top-down inhibition of pre-active responses. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease. Is valaciclovir safe and effective for EBV suppression in COPD? The Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks. The primary efficacy outcome was sputum EBV suppression (defined as ≥ 90% sputum viral load reduction) at week 8. The primary safety outcome was the incidence of serious adverse reactions. Secondary outcome measures were FEV 1 and drug tolerability. Exploratory outcomes included changes in quality of life, sputum cell counts, and cytokines. From November 2, 2018, through March 12, 2020, 84 patients were assigned randomly (n = 43 to valaciclovir). Eighty-one patients completed trial follow-up and were included in the intention-to-treat analysis of the primary outcome. A greater number of participants in the valaciclovir group achieved EBV suppression (n = 36 [87.8%] vs n = 17 [42.5%]; P <.001). Valaciclovir was associated with a significant reduction in sputum EBV titer compared with placebo (–90,404 copies/mL [interquartile range, –298,000 to –15,200 copies/mL] vs –3,940 copies/mL [interquartile range, –114,400 to 50,150 copies/mL]; P =.002). A statistically nonsignificant 24-mL numerical FEV 1 increase was shown in the valaciclovir group (difference, –44 mL [95% CI, –150 to 62 mL]; P =.41). However, a reduction in sputum white cell count was noted in the valaciclovir group compared with the placebo group (difference, 2.89 [95% CI, 1.5 × 106-7.4 × 106]; P =.003). Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. ClinicalTrials.gov; No.: NCT03699904; URL: www.clinicaltrials.gov [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the efficacy and safety of Kolofort® (a complex medicine containing technologically processed forms of antibodies to S-100 protein, tumor necrosis factor-α and histamine) in the management of functional dyspepsia (FD) in outpatient clinical practice.Methods: Outpatients (N = 309) at the age of 18–45 in whom FD was diagnosed according to the Rome IV criteria were enrolled in a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients were randomized in two groups receiving Kolofort® or placebo 2 tablets tid for 8 weeks. The primary endpoint of the study was a change in the FD symptoms severity score according to the Gastrointestinal symptom score (GIS) at week 8. ITT and [PP] analysis were performed.Results: at week 8 the reduction in GIS sum score was observed in Kolofort® group and placebo group (by 7.2 ± 3.3 [7.2 ± 3.4] and 6.3 ± 4.6 [6.2 ± 4.5], respectively, p = 0.041 [0.039]). The proportion of cases with GIS score reduction by ≥4 was 88,1 % [88.6 %] and 79.1 % [79.6 %] in Kolofort® group and placebo group, respectively (p = 0.046 [p = 0.051]). None of the patients in Kolofort® group had progression of FD symptoms or required additional therapy. There were 29 adverse events (AEs) recorded in 25 patients including 16 cases in 13 (8.6 %) patients in Kolofort® group and 13 AEs in 12 (7.6 %) patients in placebo group.Conclusion: the clinical trial demonstrates the positive effect of Kolofort® in FD with a favorable safety profile.

Background: Procyanidins have antioxidative properties that may protect against age-related brain oxidative stress. Previous studies indicated that procyanidin-rich foods could improve cognitive function and prevent neurodegenerative diseases. This study hypothesized that grape seed procyanidins extract (GSPE) would have a favorable effect on cognitive function in elderly people with mild cognitive impairment (MCI). Methods: A community-based, randomized, double-blind, placebo-controlled trial was conducted. Participants aged 60 years or older with MCI were randomly assigned into the GSPE group (n = 35, 320 mg/d) or placebo group (n = 36), and received capsules for 6 months. Cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The change in MoCA scores between groups were tested by the time ✕ treatment interaction in mixed-design ANOVA. Results: After 6 months of intervention, the MoCA score was higher than the baseline both in the intervention group and placebo control group, while the there was no significant difference for mean change in MoCA score from baseline between the intervention group and the placebo group (2.35 ± 3.20 vs. 1.28 ± 2.93, P = 0.192). Conclusions: Present study showed that 6-month supplementation with GSPE did not significantly improve cognitive function in subjects with MCI. Further investigations regarding the longer-term intervention effect of procyanidins extract on mild or moderate cognitive disorders are needed.

Objectives The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. Methods This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint. Results Thirty-five participants were randomized to placebo (n  = 8), GSK2330811 100 mg (n  = 3) or GSK2330811 300 mg (n  = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups. Conclusion Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc. Trial registration number ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95. [ABSTRACT FROM AUTHOR]

Abstract Background Low back and neck pain are a leading cause of disease burden globally. Opioids are recommended in guidelines for acute low back and neck pain; however, there is a lack of compelling efficacy data to support this. Methods The OPAL trial is a prospectively registered, triple-blinded, randomised, placebo-controlled trial. Patients with acute (≤12 weeks duration) back and/or neck pain receive guideline care plus either an opioid (oxycodone + naloxone, up to 20 mg per day) or a placebo for up to 6 weeks or earlier, if pain is resolved. The primary outcome is pain measured using the Pain Severity Score of the Brief Pain Inventory with the primary time point being 6 weeks. Secondary outcomes include physical function, time to recovery, quality of life, adverse events and risk of opioid misuse. Outcomes are collected at weeks 2, 4, 6, 12, 26 and 52. Analysis will be done on an intention-to-treat principle. p values of

Despite the availability of vaccinations, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause Coronavirus Disease 2019 (COVID-19) infection with a spectrum of disease in the acute setting. Transmission, infection, and severe disease remain common. There is a critical need to establish treatment regimens in the ambulatory setting that can reduce symptom burden and potentially prevent progression to severe disease and death. Many existing medicines previously approved for other uses may have benefit but remain unproven in informative clinical trials.

Background: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. Methods: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. Results: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44–64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24–0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). Conclusion: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19. [ABSTRACT FROM AUTHOR]

Background: Phosphatidylserine (PS) and α-Linolenic acid (ALA), are positively associated with cognitive function, but their combination effects and possible mechanisms remain unclear. We aimed to explore the effects on cognition and potential mechanism of the supplements., Methods: This randomized, double-blind, placebo-controlled trial recruited 190 MCI patients in Tianjin, China, and randomly assigned in intervention group and placebo group. Each group consumed two capsules every day for 12 months. Each capsule for intervention group contains 144 mg ALA, 31.5 mg PS and 3.6 mg Ginkgo total flavonoids as main functional components, with 0.48 mg Vitamin B 1 (as thiamine hydrochloride), 0.48 mg Vitamin B 6 (as pyridoxine hydrochloride) and 90 μg folic acid as supplement. Capsules for placebo group were identical but contain no active ingredients. Cognitive function, serum n-3 polyunsaturated fatty acids (PUFAs) and neurotransmitters were assessed at baseline and 12 months. Linear mixed effects model and causal mediation analysis were conducted to explore the effects and potential mechanism of the intervention., Results: A total of 190 participants (mean [SD] age, 67.95 [5.62] years; 70 (36.8 %) male and 120 (63.2 %) female) were randomized to the placebo group (n = 95) and intervention group (n = 95). Compared with placebo group, the intervention group had statistically significant improvements in arithmetic testing (β, 0.688; 95 % CI, 0.103-1.274), the similarity test (β, 1.070; 95 % CI, 0.472-1.667) and short-term memory (β, 0.600; 95 % CI, 0.399-0.800). Besides, the intervention group had statistically significant increases in serum ALA (β, 1.620; 95 % CI, 0.967-2.265), DHA (β, 2.797; 95 % CI, 1.075-4.532), EPA (β, 1.472; 95 % CI, 0.296-2.643), acetylcholine (β, 0.441; 95 % CI, 0.415-0.468), GABA (β, 0.009; 95 % CI, 0.001-0.016) and 5-HT (β, 0.160; 95 % CI, 0.081-0.238) compared to the placebo group. And the intervention may improve short-term memory by increasing serum ALA levels (average causal mediation effect = 0.132, 95 % CI, 0.053-0.225) with 19.7 % mediation proportion., Conclusions: This food supplement containing phosphatidylserine could improve different cognitive functions of MCI patients, especially short-term memory, and increase serum n-3 PUFAs and neurotransmitters levels. Serum ALA level might play a mediation role., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, financial or otherwise., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease.Methods: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial.Randomisation: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated.Blinding: Participants and investigators will both be blinded to treatment allocation (double-blind).Discussion: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease.Trial Registration: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021. [ABSTRACT FROM AUTHOR]

Abstract Objectives The objective of this trial is to assess whether early antiviral therapy in outpatients with COVID-19 with either favipiravir plus lopinavir/ritonavir, lopinavir/ritonavir alone, or favipiravir alone, is associated with a decrease in viral load of SARS-CoV-2 compared with placebo. Trial design FLARE is a phase IIA randomised, double-blind, 2x2 factorial placebo-controlled, interventional trial. Participants This trial is being conducted in the United Kingdom, with Royal Free Hospital, London as the lead site. Participants are non-hospitalised adults with highly suspected COVID-19 within the first 5 days of symptom onset, or who have tested positive with SARS-CoV-2 causing COVID-19 within the first 7 days of symptom onset, or who are asymptomatic but tested positive for SARS-CoV-2 for the first time within the last 48 hours. Inclusion criteria are as follows: 1. Any adult with the following: Symptoms compatible with COVID-19 disease (Fever >37.8°C on at least one occasion AND either cough and/ or anosmia) within the first 5 days of symptom onset (date/time of enrolment must be within the first 5 days of symptom onset) OR ANY symptoms compatible with COVID-19 disease (may include, but are not limited to fever, cough, shortness of breath, malaise, myalgia, headache, coryza) and tested positive for SARS-CoV-2 within the first 7 days of symptom onset) (date/time of enrolment must be within the first 7 days of symptom onset) OR no symptoms but tested positive for SARS-CoV-2 within the last 48 hours (date/time of test must be within 48 hours of enrolment) 2. Male or female aged 18 years to 70 years old inclusive at screening 3. Willing and able to take daily saliva samples 4. Able to provide full informed consent and willing to comply with trial-related procedures Exclusion criteria are as follows: 1. Known hypersensitivity to any of the active ingredients or excipients in favipiravir and matched placebo, and in lopinavir/ritonavir and matched placebo (See Appendix 2) 2. Chronic liver disease at screening (known cirrhosis of any aetiology, chronic hepatitis (e.g. autoimmune, viral, steatohepatitis), cholangitis or any known elevation of liver aminotransferases with AST or ALT > 3 X ULN)* 3. Chronic kidney disease (stage 3 or beyond) at screening: eGFR < 60 ml/min/1.73m2 * 4. HIV infection, if untreated, detectable viral load or on protease inhibitor therapy 5. Any clinical condition which the investigator considers would make the participant unsuitable for the trial 6. Concomitant medications known to interact with favipiravir and matched placebo, and with lopinavir/ritonavir and matched placebo, and carry risk of toxicity for the participant 7. Current severe illness requiring hospitalisation 8. Pregnancy and/ or breastfeeding 9. Eligible female participants of childbearing potential and male participants with a partner of childbearing potential not willing to use highly effective contraceptive measures during the trial and within the time point specified following last trial treatment dose. 10. Participants enrolled in any other interventional drug or vaccine trial (co-enrolment in observational studies is acceptable) 11. Participants who have received the COVID-19 vaccine *Considering the importance of early treatment of COVID-19 to impact viral load, the absence of known chronic liver/ kidney disease will be confirmed verbally by the participant during pre-screening and Screening/Baseline visit. Safety blood samples will be collected at Screening/Baseline visit (Day 1) and test results will be examined as soon as they become available and within 24 hours. Intervention and comparator Participants will be randomised 1:1:1:1 using a concealed online minimisation process into one of the following four arms: Arm 1: Favipiravir + Lopinavir/ritonavir Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 2: Favipiravir + Lopinavir/ritonavir placebo Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 3: Favipiravir placebo + Lopinavir/ritonavir Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 4: Favipiravir placebo + Lopinavir/ritonavir placebo Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Main outcomes The primary outcome is upper respiratory tract viral load at Day 5. Secondary outcomes: Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy Proportion of participants with undetectable stool viral load after 7 days of therapy Rate of decrease in upper respiratory tract viral load during 7 days of therapy Duration of fever following commencement of trial medications Proportion of participants with hepatotoxicity after 7 days of therapy Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation Proportion of participants admitted to hospital with COVID-19 related illness Proportion of participants admitted to ICU with COVID-19 related illness Proportion of participants who have died with COVID-19 related illness Pharmacokinetic and pharmacodynamic analysis of favipiravir Exploratory: Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 Randomisation Participants will be randomised 1:1:1:1 using a concealed online minimisation process, with the following factors: trial site, age (≤ 55 vs > 55 years old), gender, obesity (BMI

Study Objectives: The purpose of this study was to determine the effects of daytime transcranial direct current stimulation (tDCS) on sleep electroencephalogram (EEG) in patients with depression. Methods: The study was a double-blinded, randomized, controlled clinical trial. A total of 37 patients diagnosed with a major depression were recruited; 19 patients (13 females and 6 males mean age 44.79 ± 15.25 years) received tDCS active stimulation and 18 patients (9 females and 9 males; mean age 43.61 ± 11.89 years) received sham stimulation. Ten sessions of daytime tDCS were administered with the anode over F3 and the cathode over F4. Each session delivered a 2 mA current for 30 min per 10 working days. Hamilton-24 and Montgomery scales were used to assess the severity of depression, and polysomnography (PSG) was used to assess sleep structure and EEG complexity. Eight intrinsic mode functions (IMFs) were computed from each EEG signal in a channel. The sample entropy of the cumulative sum of the IMFs were computed to acquire high-dimensional multi-scale complexity information of EEG signals. Results: The complexity of Rapid Eye Movement (REM) EEG signals significantly decreased intrinsic multi-scale entropy (iMSE) (1.732 ± 0.057 vs. 1.605 ± 0.046, P = 0.0004 in the case of the C4 channel, IMF 1:4 and scale 7) after tDCS active stimulation. The complexity of the REM EEG signals significantly increased iMSE (1.464 ± 0.101 vs. 1.611 ± 0.085, P = 0.001 for C4 channel, IMF 1:4 and scale 7) after tDCS sham stimulation. There was no significant difference in the Hamilton-24 (P = 0.988), Montgomery scale score (P = 0.726), and sleep structure (N1% P = 0.383; N2% P = 0.716; N3% P = 0.772) between the two groups after treatment. Conclusion: Daytime tDCS changed the complexity of sleep in the REM stage, and presented as decreased intrinsic multi-scale entropy, while no changes in sleep structure occurred. This finding indicated that daytime tDCS may be an effective method to improve sleep quality in depressed patients. Trial registration This trial has been registered at the ClinicalTrials.gov (protocol ID: TCHIRB-10409114, in progress). [ABSTRACT FROM AUTHOR]

Introduction: Patients undergoing lumbar spine surgery often suffer from severe radicular postoperative pain leading to the prescription of high-dose opioids. In Integrative Medicine, Hypericum perforatum is known as a remedy to relieve pain caused by nerve damage. Objectives: This trial investigated whether homeopathic Hypericum leads to a reduction in postoperative pain and a decrease in pain medication compared with placebo. Design: Randomized double blind, monocentric, placebo controlled clinical trial. Settings/Location: Department of Neurosurgery, Community Hospital Herdecke. Subjects: Inpatients undergoing lumbar sequestrectomy surgery. Interventions: Homeopathic treatment versus placebo in addition to usual pain management. Outcomes Measures: Primary endpoint was pain relief measured with a visual analog scale. Secondary endpoints were the reduction of inpatient postoperative analgesic medication and change in sensory and affective pain perception. Results: Baseline characteristics were comparable between the groups. Pain perception between baseline and day 3 did not significantly differ between the study arms. With respect to pain medication, total morphine equivalent doses did not differ significantly. However, a statistical trend and a moderate effect (d = 0.432) in the decrease of pain medication consumption in favor of the Hypericum group was observed. Conclusion: This is the first trial of homeopathy that evaluated the efficacy of Hypericum C200 after lumbar monosegmental spinal sequestrectomy. Although no significant differences between the groups could be shown, we found that patients who took potentiated Hypericum in addition to usual pain management showed lower consumption of analgesics. Further investigations, especially with regard to pain medication, should follow to better classify the described analgesic reduction. Clinical Trial Registration Number: German Clinical Trials Register No: DRKS00007913. [ABSTRACT FROM AUTHOR]

Objective: L-theanine, a non-proteinic amino acid found in tea, is known to enhance attention particularly in high doses, with no reported adverse effects. We aimed to determine whether oral administration of L-theanine acutely enhances neurophysiological measures of selective attention in a dose-dependent manner. Methods: In a double-blind, placebo-controlled, counterbalanced, 4-way crossover study in a group of 27 healthy young adults, we compared the effects of 3 doses of L-theanine (100, 200 and 400 mg) with a placebo (distilled water) on latencies of amplitudes of attentive and pre-attentive cognitive event-related potentials (ERPs) recorded in an auditory stimulus discrimination task, before and 50 min after dosing. Results: Compared to the placebo, 400 mg of theanine showed a significant reduction in the latency of the parietal P3b ERP component (p < 0.05), whereas no significant changes were observed with lower doses. A subsequent exploratory regression showed that each 100-mg increase in dose reduces the P3b latency by 4 ms (p < 0.05). No dose–response effect was observed in P3b amplitude, pre-attentive ERP components or reaction time. Discussion: The findings indicate L-theanine can increase attentional processing of auditory information in a dose-dependent manner. The linear dose–response attentional effects we observed warrant further studies with higher doses of L-theanine. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorders (AUDs) are common in men who have sex with men (MSM) and transgender women (TGW) in Peru and undermine antiretroviral therapy (ART) adherence. Oral naltrexone (NTX) is an evidence-based treatment for AUD that has not been assessed in cotreating AUD in MSM/TGW with HIV. Setting and Design: A multi-site, randomized, double-blind, placebo-controlled trial among MSM/TGW with AUD and newly diagnosed with HIV in Lima, Peru. Methods: Newly diagnosed MSM/TGW with HIV and AUD were prescribed a single-treatment regimen of EFV/TDF/FTC from 2014 to 2015 and randomized 2:1 to oral NTX (N = 103) or placebo (N = 53) for 24 weeks. The primary and secondary outcomes were proportion achieving viral suppression (VS: HIV-1 RNA < 400 copies/mL) or maximal viral suppression (MVS: HIV-1 RNA < 40 copies/mL) at 24 weeks. Results: There were no significant differences between the arms in VS (81.6% NTX arm vs 75.5% placebo arm; P = 0.37) or MVS (61.2% NTX arm vs 66.0% placebo arm; P = 0.48). Adherence to study medication was low (mean = 34.6%) overall with only 21.4% of participants meeting recommended adherence levels (>=80% daily doses/month). Participants allocated to NTX had significantly lower adherence compared with placebo for both the first and second 12-week study periods, respectively (44.0% vs 35.2%, P = 0.04; 31.4% vs 35.2%, P = 0.03). Conclusions: Findings are inconclusive regarding the use of NTX for treatment of AUD in MSM/TGW newly diagnosed with HIV. VS and MVS levels were high irrespective of allocation. Adherence to study medication was low, requiring further exploration of strategies to optimize adherence to NTX as AUD treatment. [ABSTRACT FROM AUTHOR]

Background: Low back and neck pain are a leading cause of disease burden globally. Opioids are recommended in guidelines for acute low back and neck pain; however, there is a lack of compelling efficacy data to support this.Methods: The OPAL trial is a prospectively registered, triple-blinded, randomised, placebo-controlled trial. Patients with acute (≤12 weeks duration) back and/or neck pain receive guideline care plus either an opioid (oxycodone + naloxone, up to 20 mg per day) or a placebo for up to 6 weeks or earlier, if pain is resolved. The primary outcome is pain measured using the Pain Severity Score of the Brief Pain Inventory with the primary time point being 6 weeks. Secondary outcomes include physical function, time to recovery, quality of life, adverse events and risk of opioid misuse. Outcomes are collected at weeks 2, 4, 6, 12, 26 and 52. Analysis will be done on an intention-to-treat principle. p values of < 0.05 will be considered significant and 95% confidence intervals will be reported. Repeated-measures linear mixed models will be used to assess the effect of the treatment group on the primary outcome and continuous secondary outcomes. Adverse events will be compared between groups using Fisher's exact test. Cost-effectiveness analyses will be conducted if a treatment effect on pain is seen at week 6. Subgroup analyses will be performed to assess whether pain duration and pain location are treatment effect modifiers.Discussion: The OPAL trial will provide important evidence about whether a short course of opioids is effective in the treatment of acute non-specific low back and/or neck pain. This pre-specified statistical analysis plan details the methodology for the analysis of the OPAL trial results.Trial Registration: ACTRN12615000775516 . The trial has completed recruitment. Follow-up on the last patient will be completed in March 2022. [ABSTRACT FROM AUTHOR]

Abstract Background Non-nutritive sweeteners (NNS) are widely consumed by humans due to their apparent innocuity, especially sucralose. However, several studies link sucralose consumption to weight gain and metabolic derangements, although data are still contradictory. Objective To determine the effect of acute and chronic consumption of sucralose on insulin and glucose profiles in young healthy adults. Material and methods This was a randomized, parallel, double-blind, placebo-controlled trial conducted in healthy young adults from 18 to 35 years old, without insulin resistance. A hundred thirty seven participants were randomized into three groups: a) volunteers receiving 48 mg sucralose, b) volunteers receiving 96 mg sucralose, and c) controls receiving water as placebo. All participants underwent a 3-h oral glucose tolerance test (OGTT) preceded by consuming sucralose or placebo 15 min before glucose load, at two time points: week zero (Wk0) and week ten (Wk10). Serum insulin and glucose were measured every 15 min during both OGTTs. Results Compared to Wk0, consumption of sucralose for 10 weeks provoked 1) increased insulin concentrations at 0 min (7.5 ± 3.4 vs 8.8 ± 4.1 μIU/mL; p = 0.01), 30 min (91.3 ± 56.2 vs 110.1 ± 49.4 μIU/mL; p = 0.05), 105 min (47.7 ± 24.4 vs 64.3 ± 48.2 μIU/mL; p = 0.04) and 120 min (44.8 ± 22.1 vs 63.1 ± 47.8 μIU/mL; p = 0.01) in the 48 mg sucralose group; 2) increased blood glucose at − 15 min (87.9 ± 4.6 vs 91.4 ± 5.4 mg/dL; p = 0.003), 0 min (88.7 ± 4 vs 91.3 ± 6 mg/dL; p = 0.04) and 120 min (95.2 ± 23.7 vs 106.9 ± 19.5 mg/dL; p = 0.009) in the 48 mg sucralose group; 3) increased area under the curve (AUC) of insulin in both 48 and 96 mg sucralose groups (9262 vs 11,398; p = 0.02 and 6962 vs 8394; p = 0.12, respectively); and 4) reduced Matsuda index in the 48 mg sucralose group (6.04 ± 3.19 vs 4.86 ± 2.13; p = 0.01). Conclusions These data show that chronic consumption of sucralose can affect insulin and glucose responses in non-insulin resistant healthy young adults with normal body mass index (between 18.5 and 24.9 kg/m2), however, the effects are not consistent with dose; further research is required. Clinical trial registry NCT03703141 .

Abstract Background Ketogenic and low-glycemic-index diets are effective in treating drug-resistant seizures in children with Angelman syndrome. Cognition, mobility, sleep, and gastrointestinal health are intrinsically linked to seizure activity and overall quality of life. Ketogenic and low-glycemic diets restrict carbohydrate consumption and stabilize blood glucose levels. The ketogenic diet induces ketosis, a metabolic state where ketone bodies are preferentially used for fuel. The use of exogenous ketones in promoting ketosis in Angelman syndrome has not been previously studied. The study formulation evaluated herein contains the exogenous ketone beta-hydroxybutyrate to rapidly shift the body towards ketosis, resulting in enhanced metabolic efficiency. Methods/design This is a 16-week, randomized, double-blind, placebo-controlled, crossover study to assess the safety and tolerability of a nutritional formula containing exogenous ketones. It also examines the potential for exogenous ketones to improve the patient’s nutritional status which can impact the physiologic, symptomatic, and health outcome liabilities of living with Angelman syndrome. Discussion This manuscript outlines the rationale for a study designed to be the first to provide data on nutritional approaches for patients with Angelman syndrome using exogenous ketones. Trial registration ClinicalTrials.gov, ID: NCT03644693. Registered on 23 August 2018. Last updated on 23 August 2018.

Background: In the early phase of the pandemic, some guidelines recommended the use of corticosteroids for critically ill patients with COVID‐19, whereas others recommended against the use despite lack of firm evidence of either benefit or harm. In the COVID STEROID trial, we aimed to assess the effects of low‐dose hydrocortisone on patient‐centred outcomes in adults with COVID‐19 and severe hypoxia. Methods: In this multicentre, parallel‐group, placebo‐controlled, blinded, centrally randomised, stratified clinical trial, we randomly assigned adults with confirmed COVID‐19 and severe hypoxia (use of mechanical ventilation or supplementary oxygen with a flow of at least 10 L/min) to either hydrocortisone (200 mg/d) vs a matching placebo for 7 days or until hospital discharge. The primary outcome was the number of days alive without life support at day 28 after randomisation. Results: The trial was terminated early when 30 out of 1000 participants had been enrolled because of external evidence indicating benefit from corticosteroids in severe COVID‐19. At day 28, the median number of days alive without life support in the hydrocortisone vs placebo group were 7 vs 10 (adjusted mean difference: −1.1 days, 95% CI −9.5 to 7.3, P =.79); mortality was 6/16 vs 2/14; and the number of serious adverse reactions 1/16 vs 0/14. Conclusions: In this trial of adults with COVID‐19 and severe hypoxia, we were unable to provide precise estimates of the benefits and harms of hydrocortisone as compared with placebo as only 3% of the planned sample size were enrolled. Trial registration: ClinicalTrials.gov: NCT04348305. European Union Drug Regulation Authorities Clinical Trials (EudraCT) Database: 2020‐001395‐15. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the effects of folic acid (FA) combined with a docosahexaenoic acid (DHA) intervention on the cognitive function and inflammatory cytokines in elderly subjects with mild cognitive impairment (MCI). Methods: This randomized, double-blind, placebo-controlled trial recruited 240 individuals with MCI in Tianjin, China, and randomly allocated into 4 groups: FA + DHA (FA 800 μg/d + DHA 800 mg/d), FA (FA 800 μg/d), DHA (DHA 800 mg/d), and placebo. Cognitive function, serum folate and homocysteine (Hcy), plasma DHA and inflammatory cytokines levels were measured at baseline and 6 months. Results: Daily oral FA, DHA and their combined use for 6 months significantly improved the full-scale intelligence quotient (FSIQ) and some subtests of Wechsler Adult Intelligence Scale compared to the placebo. The increases of FSIQ, arithmetic, picture completion scores in the FA group and picture completion, block design scores in the DHA group were significantly less than that in the FA combined DHA group (P < 0.05). Meanwhile, daily oral FA, DHA and their combined use for 6 months significantly decreased plasma inflammatory cytokines compared to the placebo. The changes of interleukin-1β levels in the FA group and interleukin-6 levels in the DHA group were significantly less than that in the FA + DHA group (P < 0.05). Conclusions: Daily oral FA, DHA and their combined use for 6 months can significantly improve cognitive function and decrease plasma inflammatory cytokines in MCI individuals. The combination of FA and DHA was more beneficial than each individual nutrient on their own. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this trial is to assess whether early antiviral therapy in outpatients with COVID-19 with either favipiravir plus lopinavir/ritonavir, lopinavir/ritonavir alone, or favipiravir alone, is associated with a decrease in viral load of SARS-CoV-2 compared with placebo.Trial Design: FLARE is a phase IIA randomised, double-blind, 2x2 factorial placebo-controlled, interventional trial.Participants: This trial is being conducted in the United Kingdom, with Royal Free Hospital, London as the lead site. Participants are non-hospitalised adults with highly suspected COVID-19 within the first 5 days of symptom onset, or who have tested positive with SARS-CoV-2 causing COVID-19 within the first 7 days of symptom onset, or who are asymptomatic but tested positive for SARS-CoV-2 for the first time within the last 48 hours. Inclusion criteria are as follows: 1. Any adult with the following: Symptoms compatible with COVID-19 disease (Fever >37.8°C on at least one occasion AND either cough and/ or anosmia) within the first 5 days of symptom onset (date/time of enrolment must be within the first 5 days of symptom onset) OR ANY symptoms compatible with COVID-19 disease (may include, but are not limited to fever, cough, shortness of breath, malaise, myalgia, headache, coryza) and tested positive for SARS-CoV-2 within the first 7 days of symptom onset) (date/time of enrolment must be within the first 7 days of symptom onset) OR no symptoms but tested positive for SARS-CoV-2 within the last 48 hours (date/time of test must be within 48 hours of enrolment) 2. Male or female aged 18 years to 70 years old inclusive at screening 3. Willing and able to take daily saliva samples 4. Able to provide full informed consent and willing to comply with trial-related procedures Exclusion criteria are as follows: 1. Known hypersensitivity to any of the active ingredients or excipients in favipiravir and matched placebo, and in lopinavir/ritonavir and matched placebo (See Appendix 2) 2. Chronic liver disease at screening (known cirrhosis of any aetiology, chronic hepatitis (e.g. autoimmune, viral, steatohepatitis), cholangitis or any known elevation of liver aminotransferases with AST or ALT > 3 X ULN)* 3. Chronic kidney disease (stage 3 or beyond) at screening: eGFR < 60 ml/min/1.73m2 * 4. HIV infection, if untreated, detectable viral load or on protease inhibitor therapy 5. Any clinical condition which the investigator considers would make the participant unsuitable for the trial 6. Concomitant medications known to interact with favipiravir and matched placebo, and with lopinavir/ritonavir and matched placebo, and carry risk of toxicity for the participant 7. Current severe illness requiring hospitalisation 8. Pregnancy and/ or breastfeeding 9. Eligible female participants of childbearing potential and male participants with a partner of childbearing potential not willing to use highly effective contraceptive measures during the trial and within the time point specified following last trial treatment dose. 10. Participants enrolled in any other interventional drug or vaccine trial (co-enrolment in observational studies is acceptable) 11. Participants who have received the COVID-19 vaccine *Considering the importance of early treatment of COVID-19 to impact viral load, the absence of known chronic liver/ kidney disease will be confirmed verbally by the participant during pre-screening and Screening/Baseline visit. Safety blood samples will be collected at Screening/Baseline visit (Day 1) and test results will be examined as soon as they become available and within 24 hours.Intervention and Comparator: Participants will be randomised 1:1:1:1 using a concealed online minimisation process into one of the following four arms: Arm 1: Favipiravir + Lopinavir/ritonavir Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 2: Favipiravir + Lopinavir/ritonavir placebo Oral favipiravir at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 3: Favipiravir placebo + Lopinavir/ritonavir Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7. Arm 4: Favipiravir placebo + Lopinavir/ritonavir placebo Oral favipiravir matched placebo at 1800mg twice daily on Day 1, followed by 400mg four (4) times daily from Day 2 to Day 7 PLUS lopinavir/ritonavir matched placebo at 400mg/100mg twice daily on Day 1, followed by 200mg/50mg four (4) times daily from Day 2 to Day 7.Main Outcomes: The primary outcome is upper respiratory tract viral load at Day 5.Secondary Outcomes: Percentage of participants with undetectable upper respiratory tract viral load after 5 days of therapy Proportion of participants with undetectable stool viral load after 7 days of therapy Rate of decrease in upper respiratory tract viral load during 7 days of therapy Duration of fever following commencement of trial medications Proportion of participants with hepatotoxicity after 7 days of therapy Proportion of participants with other medication-related toxicity after 7 days of therapy and 14 days post-randomisation Proportion of participants admitted to hospital with COVID-19 related illness Proportion of participants admitted to ICU with COVID-19 related illness Proportion of participants who have died with COVID-19 related illness Pharmacokinetic and pharmacodynamic analysis of favipiravir Exploratory: Proportion of participants with deleterious or resistance-conferring mutations in SARS-CoV-2 RANDOMISATION: Participants will be randomised 1:1:1:1 using a concealed online minimisation process, with the following factors: trial site, age (≤ 55 vs > 55 years old), gender, obesity (BMI <30 vs ≥30), symptomatic or asymptomatic, current smoking status (Yes = current smoker, No = ex-smoker, never smoker), ethnicity (Caucasian, other) and presence or absence of comorbidity (defined as diabetes, hypertension, ischaemic heart disease (including previous myocardial infarction), other heart disease (arrhythmia and valvular heart disease), asthma, COPD, other chronic respiratory disease).Blinding (masking): Participants and investigators will both be blinded to treatment allocation (double-blind).Numbers To Be Randomised (sample Size): 240 participants, 60 in each arm.Trial Status: Protocol version 4.0 dated 7th January 2021. Date of first enrolment: October 2020. Recruitment is ongoing, with anticipated finish date of 31st March 2021.Trial Registration: The FLARE trial is registered with Clinicaltrials.gov, trial identifying number NCT04499677 , date of registration 4th August 2020.Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and safety of Chinese herbal external umbilicus treatment with Modified Dinggui Powder (加味丁桂散, MDGP) in patients with chronic nonbacterial prostatitis (CNP). Methods: A randomized, double-blind, placebo-controlled clinical trial was conducted among 72 patients with CNP. Participants were randomly allocated to a treatment group and a placebo group using computer software in a 1:1 ratio, and received either MDGP external umbilicus treatment (MDGP group, 36 cases) or placebo control groupl (36 cases) at acupoints Shenque (CV 8), twice a week for 4 weeks. In addtion, patients all received herbal medicine treatment twice a day for 4 weeks. The primary outcomes was the US National Institutes of Health Chronic Prostatitis Symptom Scores Index (NIH-CPSI) with a questionnaire at weeks 2 and 4. The secondary outcomes including prostatic fluid examination (white blood cells and lecithin bodies), the clinical efficacy evaluation, and the adverse events were also assessed during the entire trial. Results: The NIH-CPSI scores regarding pain or discomfort scores showed greater improvement in the MDGP group than placebo control group at weeks 2 (P0.001) and week 4 (P0.004), respectively. NIH-CPSI scores of symptom severity, total scores, the amount of leukocytes number in the prostatic fifluid in the MDGP group were significantly improved (P<0.05). There was no statistical difference in the urinary symptoms, quality of life, lecithin and other scores between two groups (P>0.05). The clinical effective rate was 73.53% (25/34) in the MDGP group, which was significally higher than the placebo control group with 48.39% (25/31, P<0.05). Patients were blinded successfully, and no serious adverse effects were found during the trial. Conclusion: A 4-week course of umbilicus treatment with modified Dinggui Powder seems to relieve pain and symptom severity effectively and increase the amount of leukocytes number in patients with CNP (Trial registration No. ChiCTR1800014687). [ABSTRACT FROM AUTHOR]

Prospective, double-blind, randomized, placebo-controlled studies are considered to provide the highest quality of interventional evidence. This meta-analysis summarizes the frequencies of adverse events according to the Medical Dictionary for Regulatory Activities (MedDRA) in the placebo arms of 101 such studies in rheumatoid arthritis, including a total of 17,150 patients in the placebo arms and 37,819 patients in the verum arms. Placebo-treated patients reported more than one adverse event in a median of 55.0%, 65.5%, and 72.5% (compared to 72.3% in the verum arms), and a serious adverse event in 2.5%, 5.8%, and 8.6% (compared to 5.9% in the verum arms), with stable doses of corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs as background therapies, respectively. Odds ratios were comparable between placebo and verum arms for nausea (1.00 with 95% confidence interval (CI) 0.86–1.17), for hepatobiliary disorders (1.08 with CI 0.85–1.36), for abnormal hepatic functions (1.09 with CI 0.83–1.44), and general disorders and administration site conditions (1.39 with CI 0.95–2.03). A publication bias has to be assumed for nausea (p = 0.018; Egger’s test), diarrhoea (p = 0.022), and serious infections and infestations (p = 0.009). In conclusion, patients should be aware that “adverse events” may occur even with placebo medication, independent from an additional verum medication added to the background therapy. Further studies are warranted to respect and overcome the psychological and other issues related to these placebo-related “adverse events”.

Abstract Background The estimated annual global burden of miscarriage is 33 million out of 210 million pregnancies. Many women undergoing miscarriage have surgery to remove pregnancy tissues, resulting in miscarriage surgery being one of the most common operations performed in hospitals in low-income countries. Infection is a serious consequence and can result in serious illness and death. In low-income settings, the infection rate following miscarriage surgery has been reported to be high. Good quality evidence on the use of prophylactic antibiotics for surgical miscarriage management is not available. Given that miscarriage surgery is common, and infective complications are frequent and serious, prophylactic antibiotics may offer a simple and affordable intervention to improve outcomes. Methods Eligible patients will be approached once the diagnosis of miscarriage has been made according to local practice. Once informed consent has been given, participants will be randomly allocated using a secure internet facility (1:1 ratio) to a single dose of oral doxycycline (400 mg) and metronidazole (400 mg) or placebo. Allocation will be concealed to both the patient and the healthcare providers. A total of 3400 women will be randomised, 1700 in each arm. The medication will be given approximately 2 hours before surgery, which will be provided according to local practice. The primary outcome is pelvic infection 2 weeks after surgery. Women will be invited to the hospital for a clinical assessment at 2 weeks. Secondary outcomes include overall antibiotic use, individual components of the primary outcome, death, hospital admission, unplanned consultations, blood transfusion, vomiting, diarrhoea, adverse events, anaphylaxis and allergy, duration of clinical symptoms, and days before return to usual activities. An economic evaluation will be performed to determine if prophylactic antibiotics are cost-effective. Discussion This trial will assess whether a single dose of doxycycline (400 mg) and metronidazole (400 mg) taken orally 2 hours before miscarriage surgery can reduce the incidence of pelvic infection in women up to 2 weeks after miscarriage surgery. Trial registration Registered with the ISRCTN (international standard randomised controlled trial number) registry: ISRCTN 97143849. (Registered on April 17, 2013).

Yuji Uchio,1 Hiroyuki Enomoto,2 Levent Alev,2 Yuki Kato,3 Hiroyuki Ishihara,3 Toshinaga Tsuji,4 Toshimitsu Ochiai,5 Shinichi Konno6 1Department of Orthopaedic Surgery, Shimane University School of Medicine, Shimane, Japan; 2Bio-Medicine, Medicines Development Unit, Eli Lilly Japan K.K., Kobe, Japan; 3Clinical Development Department, Shionogi & Co., Ltd., Osaka, Japan; 4Medical Affairs Department, Shionogi & Co., Ltd., Osaka, Japan; 5Biostatistics Department, Shionogi & Co., Ltd., Osaka, Japan; 6Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan Purpose: To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis. Patients and methods: Patients were randomized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double-blind manner (ClinicalTrials.gov Identifier: NCT02248480). The primary efficacy endpoint was mean change in Brief Pain Inventory pain severity (BPI-Severity) average pain. Secondary endpoints included improvement in other BPI-Severity scales, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, health-related quality of life (HRQoL) scales, range of motion of the knee joint, safety and tolerability, and structural changes on X-ray images. Results: Of the 354 randomized patients, 161 in the duloxetine group and 162 in the placebo group completed the study. BPI-Severity average pain improved significantly with duloxetine vs. placebo (−2.57 vs. −1.80; adjusted mean difference: −0.77; 95% CI: −1.11 to −0.43; P

Background: VAPOUR found vertebroplasty (V) more effective than placebo (P) in patients with severe pain and fracture duration less than 6 weeks. Exploratory analysis suggested that benefits were concentrated in the subgroup of patients with fractures ≤ 3-week duration. This difference may account for the three negative blinded trials that included few patients within this fracture time frame. Purpose: To assess the safety and efficacy of early vertebroplasty for acute painful vertebral osteoporotic fractures within 3 weeks of fracture onset in the VAPOUR study. Methods: Spearman's rank log coefficients were calculated to reassess the relationship of pain reduction from vertebroplasty and fracture duration in the VAPOUR trial. We more fully report baseline and outcome data in patients with fractures ≤ 3-week duration. Results: There were 46V and 47P patients with fractures ≤ 3-week duration. Baseline characteristics were similar. In total, 86 patients (41V, 45P) completed the 14-day questionnaire. The proportion of patients with reduction in pain from severe (NRS ≥ 7/10 was an inclusion requirement) to mild (NRS < 4) at 14 days was 21 (51%) V-group and 9 (20%) in the P-group (between-group difference 31 percentage points, 95% CI 12–50; p = 0.002). Early vertebroplasty provided greater reductions in mean NRS pain and Roland–Morris Disability. Conclusion: Analysis of this patient subgroup from the VAPOUR trial, in the context of other randomised trial evidence, suggests clinically significant benefits from early vertebroplasty if performed within 3 weeks of fracture. These slides can be retrieved from Electronic Supplementary Material. [ABSTRACT FROM AUTHOR]

Background: Non-nutritive sweeteners (NNS) are widely consumed by humans due to their apparent innocuity, especially sucralose. However, several studies link sucralose consumption to weight gain and metabolic derangements, although data are still contradictory.Objective: To determine the effect of acute and chronic consumption of sucralose on insulin and glucose profiles in young healthy adults.Material and Methods: This was a randomized, parallel, double-blind, placebo-controlled trial conducted in healthy young adults from 18 to 35 years old, without insulin resistance. A hundred thirty seven participants were randomized into three groups: a) volunteers receiving 48 mg sucralose, b) volunteers receiving 96 mg sucralose, and c) controls receiving water as placebo. All participants underwent a 3-h oral glucose tolerance test (OGTT) preceded by consuming sucralose or placebo 15 min before glucose load, at two time points: week zero (Wk0) and week ten (Wk10). Serum insulin and glucose were measured every 15 min during both OGTTs.Results: Compared to Wk0, consumption of sucralose for 10 weeks provoked 1) increased insulin concentrations at 0 min (7.5 ± 3.4 vs 8.8 ± 4.1 μIU/mL; p = 0.01), 30 min (91.3 ± 56.2 vs 110.1 ± 49.4 μIU/mL; p = 0.05), 105 min (47.7 ± 24.4 vs 64.3 ± 48.2 μIU/mL; p = 0.04) and 120 min (44.8 ± 22.1 vs 63.1 ± 47.8 μIU/mL; p = 0.01) in the 48 mg sucralose group; 2) increased blood glucose at - 15 min (87.9 ± 4.6 vs 91.4 ± 5.4 mg/dL; p = 0.003), 0 min (88.7 ± 4 vs 91.3 ± 6 mg/dL; p = 0.04) and 120 min (95.2 ± 23.7 vs 106.9 ± 19.5 mg/dL; p = 0.009) in the 48 mg sucralose group; 3) increased area under the curve (AUC) of insulin in both 48 and 96 mg sucralose groups (9262 vs 11,398; p = 0.02 and 6962 vs 8394; p = 0.12, respectively); and 4) reduced Matsuda index in the 48 mg sucralose group (6.04 ± 3.19 vs 4.86 ± 2.13; p = 0.01).Conclusions: These data show that chronic consumption of sucralose can affect insulin and glucose responses in non-insulin resistant healthy young adults with normal body mass index (between 18.5 and 24.9 kg/m2), however, the effects are not consistent with dose; further research is required.Clinical Trial Registry: NCT03703141. [ABSTRACT FROM AUTHOR]

Background: We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola Capsule for mild to moderate major depressive disorder(MDD).Methods: It is a randomized double-blind placebo-controlled clinical trial which 100 patients were randomized to 12 weeks into three groups. One of which (group A: 33 patients) received one sertraline and two placebos(0.6 g/day) tablets daily, a second (group B: 33 patients) received one sertraline and two Rhodiola capsules (0.6 g/day) daily, and a third (group C: 34 patients) received one sertraline,one placebo tablet and one tablet of Rhodiola capsule (0.3 g/day)daily. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores were examined. Significant post-treatment improvements were observed for both groups (Rhodiola Capsule) in HAMD, BDI, and CGI scores. The decline in HAMD, BDI, and CGI scores was greater for group B versus group A and C.While the CGI (versus group A) were greater for group B and C.Results: Statistically significant reductions were observed for HAM-D, BDI, and CGI scores for all treatment conditions with significant difference between groups. The decline in HAM-D, BDI, and CGI scores was greater for group B versus group C and A.Conclusions: It is concluded that the Rhodiola capsule shows anti-depressive potency in patients with depression disorder when administered in dosages of either 0.3 or 0.6 g/day over a 12-week period.Rhodiola capsule can improve the quality of life and clinical symptoms.The high doses of Rhodiola capsule are better than the lower doses. [ABSTRACT FROM AUTHOR]

Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials. [ABSTRACT FROM AUTHOR]

During the 2014 West African outbreak, a dilemma emerged about the ethics of conducting randomized placebo-controlled trials in the midst of a rapidly spreading, devastating epidemic for which there was no effective treatment. The dilemma has in fact has deep historic roots; it has appeared in several previous fearsome epidemics—during the poliomyelitis epidemic in the 1930s–1950s, and again during the AIDS epidemic in the1980s–1990s. Moreover, ethical and social questions characterizing each of these epidemics—the increased risks of withholding potentially life-saving drugs for people assigned to a control arm and the damaging effect on eroding community trust—were conceptualized beforehand in the 1925 novel Arrowsmith. A historical analysis both reaffirms that rigorous placebo-controlled trials remain indispensable tools in epidemic settings and also provides guidance on how to approach the ethical and social issues that will likely arise when these trials are carried out in future epidemic emergencies. [ABSTRACT FROM AUTHOR]

Background: Ketogenic and low-glycemic-index diets are effective in treating drug-resistant seizures in children with Angelman syndrome. Cognition, mobility, sleep, and gastrointestinal health are intrinsically linked to seizure activity and overall quality of life. Ketogenic and low-glycemic diets restrict carbohydrate consumption and stabilize blood glucose levels. The ketogenic diet induces ketosis, a metabolic state where ketone bodies are preferentially used for fuel. The use of exogenous ketones in promoting ketosis in Angelman syndrome has not been previously studied. The study formulation evaluated herein contains the exogenous ketone beta-hydroxybutyrate to rapidly shift the body towards ketosis, resulting in enhanced metabolic efficiency.Methods/design: This is a 16-week, randomized, double-blind, placebo-controlled, crossover study to assess the safety and tolerability of a nutritional formula containing exogenous ketones. It also examines the potential for exogenous ketones to improve the patient's nutritional status which can impact the physiologic, symptomatic, and health outcome liabilities of living with Angelman syndrome.Discussion: This manuscript outlines the rationale for a study designed to be the first to provide data on nutritional approaches for patients with Angelman syndrome using exogenous ketones.Trial Registration: ClinicalTrials.gov, ID: NCT03644693. Registered on 23 August 2018. Last updated on 23 August 2018. [ABSTRACT FROM AUTHOR]