Placebo-controlled Pilot Trial Research Articles

1513 Anti-IL17A, Ixekizumab, for treatment-resistant chronic venous leg ulcers: A phase II randomized, double-blind, placebo-controlled pilot trial

1513 Anti-IL17A, Ixekizumab, for treatment-resistant chronic venous leg ulcers: A phase II randomized, double-blind, placebo-controlled pilot trial

Plasma, urine, and stool metabolites in response to dietary rice bran and navy bean supplementation in adults at high-risk for colorectal cancer.

Dietary intake of whole grains and legumes and adequate physical activity (PA) have been associated with reduced colorectal cancer (CRC) risk. A single-blinded, two-arm, randomized, placebo-controlled pilot trial was implemented to evaluate the impact of a 12-week dietary intervention of rice bran + navy bean supplementation and PA education on metabolite profiles and the gut microbiome among individuals at high risk of CRC. Adults (n=20) were randomized 1:1 to dietary intervention or control. All participants received PA education at baseline. Sixteen study foods were prepared with either heat-stabilized rice bran + navy bean powder or Fibersol®-2 as a placebo. Intervention participants consumed 30 g rice bran + 30 g navy bean powder daily; those in the control group consumed 10 g placebo daily. Non-targeted metabolite profiling was performed by UPLC-MS/MS to evaluate plasma, urine, and stool at 0, 6, and 12 weeks. Stool was also analyzed for primary and secondary bile acids (BAs) and short chain fatty acids (SCFAs) by UPLC-MS/MS and microbial community structure via 16S amplicon sequencing. Two-way ANOVA was used to compare differences between groups for metabolites, and mixed models were used to compare differences between groups for BAs, SCFAs, and alpha and beta diversity measures of microbial community structure. Across biological matrices, the intervention resulted in changes to several amino acid and lipid metabolites, compared to control. There was a 2.33-fold difference in plasma (p<0.001) and a 3.33-fold difference in urine (p=0.008) for the amino acid S-methylcysteine at 12 weeks. Fold-differences to 4-methoxyphenol sulfate in plasma and urine after 6 and 12 weeks (p<0.001) was a novel result from this combined rice bran and navy bean intervention in people. A 2.98-fold difference in plasma (p=0.002) and a 17.74-fold difference in stool (p=0.026) was observed for the lipid octadecenedioylcarnitine at 12 weeks. For stool BAs, 3-oxocholic acid was increased at 12 weeks compared to control within a subset of individuals (mean difference 16.2 ug/uL, p=0.022). No significant differences were observed between groups for stool SCFAs or microbial community structure. Dietary intake of rice bran + navy beans demonstrates beneficial modulation of host and gut microbial metabolism and represents a practical and affordable means of increasing adherence to national guidelines for CRC control and prevention in a high-risk population.

Effects of Selenium Supplementation on Incidence and Severity of Preeclampsia: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial

Background: Preeclampsia is a serious hypertensive condition of pregnancy associated with high maternal and fetal morbidity and mortality. In this study, the effect of selenium supplementation on the incidence and severity of preeclampsia in pregnant women was evaluated. Methods: The present double-blind, placebo-controlled, parallel study was registered at Fatemieh Hospital of Hamadan, Iran. One hundred eighty women in the first trimesters of pregnancy were assigned to either selenium (SG, n = 90) or placebo (PG, n = 90) groups. SG and PG received 100 μg of selenium supplement or placebo per day, respectively. Results: In this study, no significant difference was observed between two groups in terms of age, body mass index, and serum selenium before the intervention (P &gt; 0.05). The incidence of preeclampsia in the SG and PG was 9 and 5, respectively (P = 0.28). There was no statistically significant difference between sex and Apgar score of neonates in the two groups (P = 0.73). The mean birth weight, systolic and diastolic blood pressure in the SG was significantly higher than PG (P = 0.003, 0.01, and 0.007, respectively). The mean gestational age in the SG was insignificantly lower than the PG (P = 0.41). After the study, preeclampsia incidence was not significant between the groups (P = 0.28). Conclusion: The administration of 100 μg of selenium supplementation in pregnant women, had no effect on decreasing preeclampsia, but it may reduce the severity of preeclampsia.

Single low-dose ketamine infusion for women with prenatal depressive symptoms undergoing cesarean delivery: A pilot randomized trial.

Ketamine is approved for antidepressant therapy, but evidence regarding its use in women with perinatal depression is lacking. Herein, we investigated the effects of low-dose ketamine in women with prenatal depressive symptoms and tested the feasibility of a future large randomized trial. This was a randomized, double-blind, placebo-controlled pilot trial. Sixty-six women with prenatal depressive symptoms who were scheduled for elective cesarean delivery were randomized to receive either low-dose ketamine (0.5 mg/kg) or placebo (normal saline). The study drugs were intravenously infused over a 40-minute period after clamping the umbilical cord. The primary outcome was depression score assessed with the Edinburgh Postnatal Depression Scale at 48 h postpartum. Among other and safety outcomes, occurrence of nausea or vomiting was observed, pain intensity was assessed with the numeric rating scale. The feasibility of implementing the protocol was also evaluated. A total of 64 parturients were included in the intention-to-treat analysis. The depression score at 48 h did not differ between groups: median 9 (interquartile range 6 to 13) with ketamine vs. 8 (6 to 10) with placebo; median difference 1, 95% CI -1 to 3; P = 0.608. The pain intensity at 4 h postpartum was less severe in the ketamine group (median difference -1, 95% CI -1 to 0, P = 0.002). Among safety outcomes, intraoperative nausea or vomiting was less common in patients given ketamine (0.0% [0/33] with ketamine vs. 21.2% [7/33] with placebo, P = 0.011). Recruitment was satisfactory and the protocol was acceptable to participants and clinicians. A single low-dose ketamine infusion did not decrease the depression score at 2 days, but reduced intraoperative nausea and vomiting and lowered pain intensity at 4 h after cesarean delivery among women with prenatal depressive symptoms. The study protocol is feasible for a large randomized trial. The study was registered with ClinicalTrials.gov (identifier: NCT03336541; 08/11/2017).

Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin – study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients

IntroductionKidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is...

Duvelisib for Critically-Ill Patients with COVID-19 Disease: An Investigator-Initiated, Randomized, Placebo-Controlled Double-Blind Pilot Trial

Background: Severe and critical COVID-19, including acute respiratory distress syndrome (ARDS), cardiomyopathy, and shock, have been associated with a 28-day mortality exceeding 50%. While dexamethasone (dex) improves survival in such patients and highlights a role for anti-inflammatory therapy, mortality remains high especially in those who do not respond initially. Phase II/III studies of the PI3K-d/g inhibitor duvelisib in patients with chronic lymphocytic leukemia or follicular lymphoma have demonstrated that duvelisib significantly downregulates expression of inflammatory cytokines and chemokines (e.g. G-CSF, GM-CSF, macrophage inflammatory protein-1 α and β). These same inflammatory molecules are upregulated in ARDS and COVID-19. Several murine models of acute lung inflammation and sepsis have demonstrated improved markers of inflammation and survival of mice treated with PI3K inhibitors. The original SAR-CoV-1 coronavirus had demonstrated the ability to hijack the PI3K signaling machinery in order to persist within human airway cells. Additionally, in the context of neoplasia, duvelisib polarizes macrophages to the M1 phenotype which has antimicrobial effector functions in contrast to the pro-inflammatory M2 phenotype. In the context of chimeric antigen receptor T (CAR T) therapy, the DiPersio lab has identified duvelisib as a potent mediator of cytokine release syndrome (CRS) without T-cell inhibition, an overlapping concept with COVID-19. We hypothesized that duvelisib could attenuate COVID-19 ARDS and CRS through M1 macrophage polarization, reduction in cytokine signaling/production, and elimination of viral persistence. Methods: We conducted a multicenter, double-blind, placebo-controlled trial in which 28 patients were randomized 1:1 to duvelisib 25mg twice daily or placebo for 10 days. Eligible patients were 18 years or older hospitalized with a primary diagnosis of COVID-19 disease with either respiratory failure (≥ 50% lung involvement by imaging, invasive or non-invasive mechanical ventilation, or extracorporeal membrane oxygenation), new cardiomyopathy, and/or shock requiring vasopressor support. All patients were required to be receiving or have received dex 6mg daily or equivalent for at least 48 hours without improvement. All patients received prophylaxis for Pneumocystis jiroveci. We monitored viral load daily using quantitative RT-PCR to assess for changes in viral replication following initiation of therapy. Primary endpoint was 28-day survival. Secondary endpoints included: 60-day survival; duration on ventilator and vasopressors; hospital and ICU length of stay; viral kinetics; and adverse events. Correlatives included impact on cytokine expression measured by multiplex panel, viral kinetics by RT-PCR, and flow-cytometry to assess immune populations at various time points during therapy. Results: Baseline and disease characteristics were well-balanced with the exception of baseline renal replacement therapy (Table 1). At day 29, 67% of those in the duvelisib arm and 62% of those in the placebo arm were alive. Secondary efficacy endpoints were comparable between the two cohorts. There was a trend toward improved 60-day OS in the duvelisib arm (60% vs. 46%, p = 0.36, Figure 1) and some patients in the treatment arm were noted to have quick radiographic and clinical improvements. Of those on ECMO at initiation 3/5 (60%) in the duvelisib arm and 1/4 (25%) in the placebo arm were successfully weaned. Adverse events (AEs) occurred at similar rates between arms. Among AEs of special interest previously reported with the use of duvelisib, one patient developed colitis ultimately deemed to be stercoral colitis and unrelated to treatment. No CMV reactivation or Pneumocystis jiroveci pneumonia occurred. Eighty percent of overall deaths were due to respiratory failure from disease progression. In the placebo arm, one patient died of Pseudomonas pneumonia and one died of cholecystitis. Conclusion: In our pilot study, duvelisib did not show improvement in 28-day survival in a critically-ill, steroid-refractory population. However, there was a trend toward improved 60-day OS. No added toxicity was observed in those receiving duvelisib. Based on comparable safety, notable improvements in select patients, and a continued unmet need in this population, we believe larger studies are justified. Correlative data will also be presented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of vitamin D3 supplementation on cellular immunity and inflammatory markers in COVID-19 patients admitted to the ICU

Vitamin D as an immunomodulator has not been studied in patients with severe COVID-19. This study aimed to estimate the efficacy of vitamin D3 supplementation on cellular immunity and inflammatory markers in patients with COVID-19 admitted to the intensive care unit (ICU). A single-center, double-blind, randomized, placebo-controlled pilot trial was conducted (N = 110). Patients were randomly assigned to receive a weekly oral dose of 60,000 IU of vitamin D3 followed by daily maintenance doses of 5000 IU (n = 55) or placebo (n = 55). Primary outcomes were lymphocyte counts, natural killer (NK) and natural killer T (NKT) cell counts, neutrophil-to-lymphocyte ratio (NLR), and serum levels of inflammatory markers on 7th day of treatment. On day 7, patients in the vitamin D3 group displayed significantly higher NK and NKT cell counts and NLR than those in the placebo group did. The mortality rate (37% vs 50%, P = 0.16), need for mechanical ventilation (63% vs 69%, P = 0.58), incidence of nosocomial infection (60% vs 41%, P = 0.05) did not significantly differ between groups. Vitamin D3 supplementation, compared with placebo, significantly increased lymphocyte counts, but did not translate into reduced mortality in ICU.Trial Registration: ClinicalTrials.gov Identifier: NCT05092698.

Efficacy of Phellinus linteus extract on immunity enhancement: A CONSORT-randomized, double-blind, placebo-controlled pilot trial.

Background:Immunity is a major system that defends the human body from the outside. Recently, interest in foods related to immunity has been increasing.Methods:The purpose of this clinical trial was to determine the safety and efficacy of Phellinus linteus (PL) extract in improving immune function. A total of 30 participants were randomly assigned to 3 groups: the PL1000 group (n = 10) took 1000 mg of PL extract and 1000 mg of dextrin per day; the PL2000 group (n = 10) took 2000 mg of PL extract per day; and the placebo group (n = 10) took 2000 mg of dextrin per day. All participants took 2 capsules twice a day for 8 weeks. We measured their natural killer cell activity and cytokine levels in blood before and after consuming the clinical trial food. Variables were also investigated to evaluate safety, such as adverse reactions, vital signs, and abnormal findings. Student t test or the Mann–Whitney U test, a paired t test or the Wilcoxon signed-rank test, a chi-square test, analysis of variance, and Kruskal–Wallis test were conducted according to the characteristics of the data to compare the differences between each group before and after participants ate the clinical trial food.Results:The natural killer cell activity and interleukin-6 levels of the PL1000 group tended to improve compared to those of the placebo group. Immunoglobulin G1, immunoglobulin G2, and immunoglobulin M levels did not show significant changes, but tended to improve in the PL1000 and PL2000 groups compared to those of the placebo group. Both the Per Protocol and Intention to Treat populations had improved validation parameters. It is safe because no hazards were found in the safety assessment.Conclusion:PL extract can help improve immunity. Evidences to conduct the main clinical trial is secured through this pilot study. A future large-scale main trial will be conducted based on this pilot study results.

Efficacy of Liriope platyphylla extract on improving respiratory function: A CONSORT-randomized, double-blind, placebo-controlled pilot trial.

Background:The respiratory system is the first line of defense against outside pollutants. Recently, respiratory health has been receiving increasing attention due to the increase in fine dust, which reduces respiratory function and increases incidence of chronic obstructive pulmonary disease, and in coronavirus pandemic, which can cause severe acute respiratory syndrome.Methods:This clinical pilot trial was designed to secure evidence for a main clinical trial and to confirm the efficacy and safety of Liriope platyphylla (LP) extract for improving respiratory function. We conducted a double-blind randomized placebo-controlled trial with 22 participants from June 30, 2021, to August 25, 2021. The primary outcome was Breathlessness, Cough, and Sputum Scale score. Secondary outcomes included forced vital capacity, forced expiratory volume at 1 second (FEV1), forced expiratory volume at 1 s/forced vital capacity ratio, cough assessment test score, chronic obstructive pulmonary disease assessment test score, peripheral blood mononuclear cell counts (white blood cells, eosinophils, T cells, and B cells), high-sensitivity C-reactive protein level, erythrocyte sedimentation rate, cytokine (interleukin-1β, interleukin-4, tumor necrosis factor-α, interleukin-6, interleukin-8, interferon-γ, and immunoglobulin E) levels, antioxidant (glutathione peroxidase and superoxide dismutase) levels, and nitric oxide level.Results:A total of 22 participants were randomly assigned to 2 groups: the LP group (n = 11), who took 1000 mg of LP extract per day, and the placebo group, who took 1000 mg of dextrin per day. Participants took 1 capsule twice a day for 4 weeks. For the Breathlessness, Cough, and Sputum Scale, the interaction between group and visit was statistically significant in a blend of analyses of variance. interleukin-8, tumor necrosis factor-α, and interferon-γ levels decreased more in the LP group than in the placebo group. The sample size required for large-scale clinical trials in the future was 50. There were no side effects.Conclusion:LP extract can enhance respiratory function. The detailed data we obtained support conducting the future main large-scale clinical trial.

Oral Preparation of Hyaluronic Acid, Chondroitin Sulfate, Curcumin, and Quercetin (Ialuril® Soft Gels) for the Prevention of LUTS after Intravesical Chemotherapy.

Intravesical chemotherapy may cause chemical cystitis and related lower urinary tract symptoms (LUTS). The aims of this study were to evaluate the efficacy and safety of an oral preparation of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin, and quercetin (Ialuril® Soft Gels) to reduce the severity of LUTS in patients with a history of bladder cancer (BCa) undergoing intravesical chemotherapy. We designed a monocentric, randomized, double-blind, placebo-controlled pilot trial. Patients referred to our institute between November 2016 and March 2018 were enrolled. All subjects had non-muscle-invasive BCa and received intravesical chemotherapy with mitomycin C (MMC). Patients were randomized 1:1 in two groups (intervention vs. control). All subjects underwent oral administration (Ialuril® Soft Gels or placebo) starting one week before the first weekly instillation and ending 30 days after the last one, subsequently starting one week before each monthly instillation and ending 14 days after it. International prostate symptom score (IPSS) and 0-100 visual analogue scale (VAS) were used to assess the efficacy of the treatment. Adverse events were also described. Patients were evaluated at baseline and after 1, 4, 7, and 13 months of intravesical chemotherapy. A total of 34 patients were enrolled. The median IPSS score was significantly lower in the intervention group compared to the control group at 4 (13 vs. 17 points; p = 0.038), 7 (10 vs. 18 points; p < 0.001), and 13 (10 vs. 17 points; p = 0.002) months. The median VAS score was significantly lower in the intervention group compared to the control group at 7 (22 vs. 37 points; p = 0.021) and 13 (20 vs. 35 points; p = 0.024) months. No AE specifically related to supplement or placebo was recorded. Oral formulation of HA, CS, quercetin, and curcumin could be an effective and safe supportive therapy against chemical cystitis in patients receiving intravesical chemotherapy for BCa.

P-629 A prospective, randomized, placebo-controlled pilot trial investigating telomere length dynamics and ovarian function in patients with diminished ovarian reserve (DOR) after danazol treatment

Abstract Study question Could the administration of a synthetic steroid -danazol- for 3 months reactivate telomerase activity and lengthen telomeres in patients with DOR? Summary answer Danazol treatment resulted in an increase of the mean leukocyte telomeric length (TL) but did not improve fertility results after the nearest ovarian stimulation (OS). What is known already A primary molecular cause of aging is telomere attrition, given that the accumulation of critically short telomeres leads organ dysfunction. Telomere shortening can be counteracted by the telomerase enzyme, which is responsible for adding deoxyribonucleotides to the linear ends of chromosomes. In patients with DOR, TL in granulosa cells (GCs) is short and telomerase activity is absent, compromising their proliferative capacity. Previuos studies have shown that estrogens can activate telomerase gene transcription through estrogen-responsive elements located in the promoter of the telomerase gene. Therefore, telomere attrition could be reduced in patients with DOR upon telomerase reactivation. Study design, size, duration This blinded, placebo-controlled pilot trial was carried out at IVIRMA Madrid clinic between February 2020 and February 2022. The study included 12 patients with DOR (AMH&amp;lt;2ng/ml) which were randomized to danazol or placebo. Patients had 12 visits for health supervision and in vitro fertilization (IVF) treatment. Both groups received danazol (400mg per day) or placebo for 3 months. As control group, 7 patients with normal ovarian reserve (AMH≥2ng/ml) were included. Participants/materials, setting, methods In both groups, blood samples were collected prior (PT) and after the treatment (AT). Luteinized GCs and blood samples were obtained during oocyte retrieval, after OS. Leukocytes were purified in Ficoll gradients and then, evaluated for TL and TRF1 levels by Quantitative Fluorescent in Situ Hybridization followed by image acquisition using high resolution confocal microscope. IVF parameters were assessed according to IVIRMA standard protocols. Main results and the role of chance A total of 19 women were recruited: 5 in the placebo group (39.8±2.7 years), 7 in Danazol group (41.0±3.0 years) and 7 in control group (39.5±3.0 years). The Danazol group showed a trend to higher mean TL in leukocytes after the treatment (108.2±37.4 versus 99±13.2 a.u., AT vs PT). Interestingly, the percentage of long telomeres also increased with treatment (15.5±0.0 versus 10.8±8.1 a.u., AT vs PT). In addition, there was a decrease of the percentage of critically short telomeres (15.7±0.0 versus 20.8±9.9 a.u. AT vs PT). In the placebo group, mean leukocyte TL and the percentage of long and short telomeres remained constant. These findings suggest that telomeres lengthen after Danazol treatment. The protein levels of TRF1, a shelterin involved in telomere protection, were similar in both Danazol and placebo groups. Regarding fertility, there were no differences in the number of antral follicles, total and MII oocytes, fertilization rate and blastocyst formation. The control group had, as expected, signficantly higher mean follicle number after OS when compared with Danazol (16.0±1.4 and 0.7±0.9, P &amp;lt; 0.0001) and placebo (16.0±1.4 and 5.0±3.8, p = 0.0127) groups, and higher numbers of total oocytes retrieved (p = 0.006; control and Danazol, and p = 0.007; control and placebo). Limitations, reasons for caution Firstly, the number of patients included in the study is limited due to strict inclusion/exclusion criteria. Secondly, because follicle growth can take up to 150 days, danazol effects could be noticeable at later OS and not only in the first OS, which was the only one studied here. Wider implications of the findings Since telomeres seem to elongate in blood samples after Danazol treatment in DOR patients, we could hypothesize that this may have a positive impact for general health, including the ovaries. Thus, danazol therapy might help improving IVF outcomes, perhaps at later OS. Trial registration number NCT04058678

Antibiotic Prophylaxis to Prevent Obesity-Related Induction Complications in Nulliparae at Term: a pilot randomized controlled trial

Women with obesity are at increased risk of complications during and after labor and delivery, including puerperal infection and cesarean delivery. As labor induction has become increasingly common, it is crucial to find ways to decrease complication rates in this high-risk population. This study aimed to explore the effect of prophylactic antibiotics during labor induction of nulliparous women with obesity on the rates of cesarean delivery and puerperal infection and to estimate the parameters needed to calculate the sample size for a larger, multicenter trial. In this randomized, placebo-controlled pilot trial, nulliparous patients with a body mass index of ≥30 kg/m2 were randomized to either prophylactic antibiotics (500 mg azithromycin for 1 dose and 2 g cefazolin every 8 hours for up to 3 doses) or placebo, administered starting at the beginning of labor induction. The exclusion criteria were known fetal anomaly, fetal demise, multifetal gestation, ruptured membranes >12 hours, infection requiring antibiotics at the start of labor induction, and/or allergy to azithromycin or beta-lactam antibiotics. The co-primary outcomes were rates of puerperal infection (composite of chorioamnionitis, endometritis, and/or cesarean delivery wound infection) and cesarean delivery. Participants were followed up for 30 days after delivery, and maternal and neonatal demographic and outcome data were collected. Proportions and 95% confidence limits were calculated for each of these outcomes. From January 2019 to May 2021, 101 patients were randomized in the class III stratum (1 patient who was randomized ultimately did not undergo labor induction). From February 2020 to May 2021, 38 and 47 patients were randomized to class I and II strata, respectively (to assess the effect of obesity class on the outcomes expected to be influenced by antibiotic prophylaxis). In the antibiotics and placebo groups, the rates of cesarean delivery were 29.0% (95% confidence interval, 19.8-38.3) and 39.8% (95% confidence interval, 29.8-49.7), respectively, and puerperal infection occurred in 8.6% (95% confidence interval, 2.9-14.3) and 9.7% (95% confidence interval, 3.7-15.7), respectively. In the subgroup with class III obesity, in the antibiotics and placebo groups, the rates of cesarean delivery were 33.3% (95% confidence interval, 20.4-47.9) and 46.0% (95% confidence interval, 32.2-59.8), respectively, and puerperal infection occurred in 7.8% (95% confidence interval, 0.5-15.2) and 10.0% (95% confidence interval, 1.7-18.3), respectively. Note that this pilot study was not powered to detect differences of this magnitude but rather to estimate parameters. The administration of prophylactic antibiotics during labor induction of nulliparous patients with obesity resulted in a 27% lower cesarean delivery rate overall and a 28% lower rate in patients with class III obesity. A larger trial is warranted to evaluate these differences.

Royal jelly plus coenzyme Q10 supplementation improves high-intensity interval exercise performance via changes in plasmatic and salivary biomarkers of oxidative stress and muscle damage in swimmers: a randomized, double-blind, placebo-controlled pilot trial.

ABSTRACTBackgroundExcessive production of free radicals caused by many types of exercise results in oxidative stress, which leads to muscle damage, fatigue, and impaired performance. Supplementation with royal jelly (RJ) or coenzyme Q10 (CoQ10) has been shown to attenuate exercise-induced oxidant stress in damaged muscle and improve various aspects of exercise performance in many but not all studies. Nevertheless, the effects of treatments based on RJ plus CoQ10 supplementation, which may be potentially beneficial for reducing oxidative stress and enhancing athletic performance, remain unexplored. This study aimed to examine whether oral RJ and CoQ10 co-supplementation could improve high-intensity interval exercise (HIIE) performance in swimmers, inhibiting exercise-induced oxidative stress and muscle damage.MethodsTwenty high-level swimmers were randomly allocated to receive either 400 mg of RJ and 60 mg of CoQ10 (RJQ) or matching placebo (PLA) once daily for 10 days. Exercise performance was evaluated at baseline, and then reassessed at day 10 of intervention, using a HIIE protocol. Diene conjugates (DC), Schiff bases (SB), and creatine kinase (CK) were also measured in blood plasma and saliva before and immediately after HIIE in both groups.ResultsHIIE performance expressed as number of points according to a single assessment system developed and approved by the International Swimming Federation (FINA points) significantly improved in RJQ group (p = 0.013) compared to PLA group. Exercise-induced increase in DC, SB, and CK levels in plasma and saliva significantly diminished only in RJQ group (p < 0.05). Regression analysis showed that oral RJQ administration for 10 days was significantly associated with reductions in HIIE-induced increases in plasmatic and salivary DC, SB, and CK levels compared to PLA. Principal component analysis revealed that swimmers treated with RJQ are grouped by both plasmatic and salivary principal components (PC) into a separate cluster compared to PLA. Strong negative correlation between the number of FINA points and plasmatic and salivary PC1 values was observed in both intervention groups.ConclusionThe improvements in swimmers’ HIIE performance were due in significant part to RJQ-induced reducing in lipid peroxidation and muscle damage in response to exercise. These findings suggest that RJQ supplementation for 10 days is potentially effective for enhancing HIIE performance and alleviating oxidant stress.AbbreviationsRJ, royal jelly; CoQ10, coenzyme Q10; HIIE, high-intensity interval exercise; DC, diene conjugates; SB, Schiff bases; CK, creatine kinase; RJQ, royal jelly plus coenzyme Q10; PLA, placebo; FINA points, points according to a single assessment system developed and approved by the International Swimming Federation; ROS, reactive oxygen species; 10H2DA, 10-hydroxy-2-decenoic acid; AMPK, 5′-AMP-activated protein kinase; FoxO3, forkhead box O3; MnSOD, manganese-superoxide dismutase; CAT, catalase; E, optical densities; PCA, principal component analysis; PC, principal component; MCFAs, medium-chain fatty acids; CaMKKβ, Ca2+/calmodulin-dependent protein kinase β; TBARS, thiobarbituric acid reactive substances; MDA, malondialdehyde.

Dietary Supplementation With Branched Chain Amino Acids to Improve Sleep in Veterans With Traumatic Brain Injury: A Randomized Double-Blind Placebo-Controlled Pilot and Feasibility Trial.

Study ObjectivesTraumatic brain injury (TBI) is associated with chronic sleep disturbances and cognitive impairment. Our prior preclinical work demonstrated dietary supplementation with branched chain amino acids (BCAA: leucine, isoleucine, and valine), precursors to de novo glutamate production, restored impairments in glutamate, orexin/hypocretin neurons, sleep, and memory in rodent models of TBI. This pilot study assessed the feasibility and preliminary efficacy of dietary supplementation with BCAA on sleep and cognition in Veterans with TBI.MethodsThirty-two Veterans with TBI were prospectively enrolled in a randomized, double-blinded, placebo-controlled trial comparing BCAA (30 g, b.i.d. for 21-days) with one of two placebo arms (microcrystalline cellulose or rice protein, both 30 g, b.i.d. for 21-days). Pre- and post-intervention outcomes included sleep measures (questionnaires, daily sleep/study diaries, and wrist actigraphy), neuropsychological testing, and blood-based biomarkers related to BCAA consumption.ResultsSix subjects withdrew from the study (2/group), leaving 26 remaining subjects who were highly adherent to the protocol (BCAA, 93%; rice protein, 96%; microcrystalline, 95%; actigraphy 87%). BCAA were well-tolerated with few side effects and no adverse events. BCAA significantly improved subjective insomnia symptoms and objective sleep latency and wake after sleep onset on actigraphy.ConclusionDietary supplementation with BCAA is a mechanism-based, promising intervention that shows feasibility, acceptability, and preliminary efficacy to treat insomnia and objective sleep disruption in Veterans with TBI. A larger scale randomized clinical trial is warranted to further evaluate the efficacy, dosing, and duration of BCAA effects on sleep and other related outcome measures in individuals with TBI.Clinical Trial Registration[http://clinicaltrials.gov/], identifier [NCT03990909].

Proteomic analysis of urinary exosomes from patients with lithium‐induced nephrogenic diabetes insipidus

Lithium (Li)‐induced Nephrogenic Diabetes Insipidus (NDI) is a large healthcare problem, which affect around 40% of patients with bipolar disorder undergoing Li treatment. NDI is characterized by the inability in the kidney to concentrate urine in response to vasopressin in the kidney collecting duct (CD). In animals, Li causes a downregulation of aquaporin‐2 and a cellular remodeling of the CD in rats resulting in a reduced fraction of principal cells relative to intercalated cells. Whether Li has similar effects in the human kidney is, however, not known. Urinary exosomes are extracellular nanovesicles derived from intracellular multivesicular bodies fused with the plasma membrane of epithelial cells lining the kidney tubular system and the urinary tract. The purpose of the first part of this study is to analyze whether the urinary rat proteome reflects the Li‐induced changes in the kidney. This is followed by proteomic analyses of urinary exosomes isolated from Li‐NDI patients.Rats were divided in three groups; controls (n=8), 2‐week Li treatment (40 mmol/kg/food, n=8) and 4‐week Li treatment (40 mmol/kg/food, n=8). Treatment with Li showed a significant increase in urine output after 2‐weeks (P&lt;0.01) and 4‐weeks (P&lt;0.05). Additionally, the rats developed severe polydipsia, with water intake significantly increased after 2‐weeks Li treatment (P&lt;0.001) and 4‐weeks Li treatment (P&lt;0.0001).Early morning urine samples from the placebo group in a previous published 12‐week placebo‐controlled pilot trial (Fotso Soh et al, 2021. A double‐blind, randomized, placebo‐controlled pilot trial of atorvastatin for nephrogenic diabetes insipidus in lithium users. Bipolar Disorders 23, 66–75) involving Li‐NDI patients (n=9) were collected. The Li‐NDI participants have been on a stable dose of Li (˃2 months) and determined to have a urinary osmolality &lt;600 mOsm/kg at baseline. In addition, urine from random healthy controls (n=6) were collected. Urine samples from the rodent study and human study were subjected to ultracentrifugation for exosome isolation and will be further processed for mass spectrometry analysis (MS/MS).

Effect of low-dose tadalafil once daily on glycemic control in patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, placebo-controlled pilot study

BackgroundPhosphodiesterase type 5 inhibitors restore nitric oxide signaling, that plays a significant role in erectile function, and appears to counteract insulin resistance in animal and human models. This study was aimed to evaluate the glycemic and metabolic effects of low-dose tadalafil once daily in patients with type 2 diabetes and erectile dysfunction.MethodsA 6-month, randomized, double-blind, placebo-controlled pilot trial was conducted. Eligible patients were randomly assigned in a ratio of 2:1 to the tadalafil 5 mg and placebo groups; all patients received either tadalafil or placebo once a day. The primary efficacy endpoint was the absolute change in glycated hemoglobin (HbA1c) levels during the 6-month study period. The secondary efficacy endpoints included metabolic parameters and erectile function.ResultsOf the 68 patients who completed this study, 45 and 23 patients were allocated to the tadalafil and placebo groups, respectively. The mean HbA1c level was significantly different between the groups over the 6-month study period (P = 0.021). After 6 months of treatment, the HbA1c decrement in the tadalafil group was greater than that in the placebo group (− 0.14 ± 0.53% vs. 0.20 ± 0.69%, P = 0.030). The International Index of Erectile Function-5 scores improvement was significantly greater in the tadalafil group than in the placebo group at 6 months (P = 0.003).ConclusionThis prospective pilot study showed that low-dose tadalafil administered once a day was effective in improving glycemic control and erectile function in patients with type 2 diabetes and erectile dysfunction.Trial registration KCT0005666

The role of duloxetine in reducing opioid consumption after thoracotomy: a prospective, randomized, double-blinded, placebo-controlled pilot trial.

Exploration of the thoracic cavity through a thoracotomy incision for thoracic malignancies is accompanied by severe, excruciating acute postoperative pain. The objective of this study is to evaluate the efficacy of perioperative duloxetine when given as part of a multimodal analgesia in reducing the dose of opioids needed to treat acute postoperative pain after thoracotomy. Sixty patients scheduled for thoracotomy were randomly assigned to one of two treatment groups. The duloxetine group (D) received duloxetine 60 mg orally two hours before the surgical procedure and 24 hours after surgery, and the placebo group (P) received oral equivalent placebo capsules during the same time schedule. The primary outcome was the postoperative consumption of narcotics. Secondary outcome measures were assessment of postoperative pain scores (VAS) during rest, walking and coughing, hemodynamic variables and development of any side effects. Total dose of morphine needed to treat postoperative pain in first 48 hours, intraoperative isoflurane concentrations, intra- and postoperative epidural infusion rates all were significantly lower in group D (P<0.001). Postoperative pain at rest (VAS-R) was significantly less frequent in group D compared to group P at all-time intervals so as during walking (VAS-W) (P<0.001). While during cough (VAS-C), it was comparable at all time point except at 12 hours which was significantly low in group D (P<0.001). The intra-, postoperative mean blood pressure and development of side effects were comparable between the two groups. Oral duloxetine used perioperatively during thoracic surgery may play an important role as multimodal analgesia for acute postoperative pain without any added side effects.

The use of photobiomodulation therapy for the prevention of chemotherapy-induced peripheral neuropathy: a randomized, placebo-controlled pilot trial (NEUROLASER trial)

PurposeThe purpose of this study was to investigate the effectiveness of photobiomodulation (PBM) therapy for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer patients.MethodsA prospective, randomized placebo-controlled pilot trial (NEUROLASER) was set up with 32 breast cancer patients who underwent chemotherapy (ClinicalTrials.gov; NCT03391271). Patients were randomized to receive PBM (n = 16) or placebo treatments (n = 16) (2 × /week) during their chemotherapy. The modified Total Neuropathy Score (mTNS), six-minute walk test (6MWT), Numeric pain Rating Scale (NRS), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Taxane (FACT/GOG-Taxane) were used to evaluate the severity of CIPN and the patients’ quality of life (QoL). Outcome measures were collected at the first chemotherapy session, 6 weeks after initiation of chemotherapy, at the final chemotherapy session, and 3 weeks after the end of chemotherapy (follow-up).ResultsThe mTNS score increased significantly over time in both the control and the PBM group. A significantly higher score for FACT/GOG-Taxane was observed in the PBM group during chemotherapy compared to the control group. Questions of the FACT/GOG-Taxane related to sensory peripheral neuropathy symptoms showed a significant increase in severeness over time in the control group, whereas they remained constant in the PBM group. At follow-up, a (borderline) significant difference was observed between both groups for the 6MWT and patients’ pain level, in benefit of the PBM group.ConclusionsThis NEUROLASER trial shows promising results concerning the prevention of CIPN with PBM in breast cancer patients. Furthermore, a better QoL was observed when treated with PBM.

Naloxegol to Prevent Constipation in ICU Adults Receiving Opioids: A Randomized Double-Blind Placebo-Controlled Pilot Trial.

Background Constipation is frequent in critically ill adults receiving opioids. Naloxegol (N), a peripherally acting mu-receptor antagonist (PAMORA), may reduce constipation. The objective of this trial was to evaluate the efficacy and safety of N to prevent constipation in ICU adults receiving opioids. Methods and Patients. In this single-center, double-blind, randomized trial, adults admitted to a medical ICU receiving IV opioids (≥100 mcg fentanyl/day), and not having any of 17 exclusion criteria, were randomized to N (25 mg) or placebo (P) daily randomized to receive N (25mg) or placebo (P) and docusate 100 mg twice daily until ICU discharge, 10 days, or diarrhea (≥3 spontaneous bowel movement (SBM)/24 hours) or a serious adverse event related to study medication. A 4-step laxative protocol was initiated when there was no SBM ≥3 days. Results Only 318 (20.6%) of the 1542 screened adults during the 1/17–10/19 enrolment period met all inclusion criteria. Of these, only 19/381 (4.9%) met all eligibility criteria. After 7 consent refusals, 12 patients were randomized. The study was stopped early due to enrolment futility. The N (n = 6) and P (n = 6) groups were similar. The time to first SBM (N 41.4 ± 31.7 vs. P 32.5 ± 25.4 hours, P = 0.56) was similar. The maximal daily abdominal pressure was significantly lower in the N group (N 10 ± 4 vs. P 13 ± 5, P = 0.002). The median (IQR) daily SOFA scores were higher in N (N 7 (4, 8) vs. P 4 (3, 5), P < 0.001). Laxative protocol use was similar (N 83.3% vs. P 66.6%; P = 0.51). Diarrhea prevalence was high but similar (N 66.6% vs. P 66.6%; P = 1.0). No patient experienced opioid withdrawal. Conclusions Important recruitment challenges exist for ICU trials evaluating the use of PAMORAs for constipation prevention. Despite being underpowered, our results suggest time to first SBM with naloxegol, if different than P, may be small. The effect of naloxegol on abdominal pressure, SOFA, and the interaction between the two requires further research.

A randomized double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in children and adolescents with autism spectrum disorder.

This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov ; NCT01302964.