Placebo-controlled Multicenter Study Research Articles

CERS1 is a biomarker of Staphylococcus aureus abundance and atopic dermatitis severity

BackgroundAtopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (i.e., dupilumab). The molecular mechanisms regulating S. aureus levels between AD subjects remain poorly understood. ObjectiveTo investigate host genes that may be predictive of S. aureus abundance and correspond with AD severity. MethodsData derived from the NIH/NIAID-funded (NCT03389893 [ADRN-09]) randomized, double-blind, and placebo-controlled multicenter study of dupilumab in adults (n=71 subjects) with moderate-severe AD. Bulk RNA-sequencing of skin biopsies (n=57 lesional, 55 non-lesional) was compared to epidermal S. aureus abundance, lipidomics, and AD clinical measures. ResultsS. aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both non-lesional (r=0.29, p=0.030) and lesional (r=0.41, p=0.0015) skin. Lesional CERS1 expression also positively correlated with AD severity (i.e., SCORing AD [SCORAD] r=0.44, p=0.0006) and skin barrier dysfunction (transepidermal water loss area under the curve [TEWL AUC] r=0.31, p=0.025) at baseline. CERS1 expression (forms C18:0-sphingolipids) was negatively associated with elongation of very long chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S. aureus abundance and ELOVL6 expression by day 21. ConclusionCERS1 is a unique molecular biomarker of S. aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

Effect of prebiotic oligosaccharides on bowel habit and the gut microbiota in children with functional constipation (Inside study): study protocol for a randomised, placebo-controlled, multi-centre trial

BackgroundFunctional constipation (FC) in children is a common gastrointestinal disorder with a worldwide-pooled prevalence of 9.5%. Complaints include infrequent bowel movements, painful defecation due to hard and/or large stools, faecal incontinence, and abdominal pain. Prebiotic oligosaccharides have been shown to relieve constipation symptoms in young adults and elderly. However, sufficient evidence is lacking linking additional prebiotic intake to improve symptoms in children with FC. We hypothesise that prebiotic oligosaccharides are able to relieve symptoms of constipation in young children as well.MethodsIn the present randomised, double-blind, placebo-controlled, multi-centre study, we will study the effects of two prebiotic oligosaccharides in comparison to placebo on constipation symptoms in children of 1–5 years (12 to 72 months) of age diagnosed with FC according to the Rome IV criteria for functional gastrointestinal disorders. The primary outcome measure will be change in stool consistency. Secondary outcomes include stool frequency and stool consistency in a number of cases (%). Tertiary outcomes include among others painful defecation, use of rescue medication, and quality of life. In addition, the impact on gut microbiome outcomes such as faecal microbiota composition and metabolites will be investigated. Participants start with a run-in period, after which they will receive supplements delivered in tins with scoops for 8 weeks, containing one of the two prebiotic oligosaccharides or placebo, followed by a 4-week wash-out period.DiscussionThis randomised double-blind, placebo-controlled multi-centre study will investigate the effectiveness of prebiotic oligosaccharides in children aged 1–5 years with FC.Trial registrationClinicalTrials.gov NCT04282551. Registered on 24 February 2020.

Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810.

Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo (Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

S460 Efficacy and Safety of IRL201104, a Novel Peptide Immunomodulator, in a Phase 2a, Double-Blind, Placebo-Controlled Multi-Center Study in Patients With Active Eosinophilic Esophagitis

S460 Efficacy and Safety of IRL201104, a Novel Peptide Immunomodulator, in a Phase 2a, Double-Blind, Placebo-Controlled Multi-Center Study in Patients With Active Eosinophilic Esophagitis

0603 Characterization of Patients Who Had ≥5% Weight Loss With FT218 (Once-Nightly Sodium Oxybate): Post Hoc Analysis From REST-ON

Abstract Introduction Narcolepsy, particularly type 1 (NT1), is often comorbid with obesity. FT218 (LUMRYZ™) is an investigational once-nightly sodium oxybate (ON-SXB) formulation whose efficacy and safety were shown in the phase 3 REST-ON clinical trial (NCT02720744). Methods REST-ON was a 13-week, randomized (1:1), double-blind, placebo-controlled multicenter study in patients ≥16 years old with NT1/NT2. Stable concomitant stimulant use was permitted. A post hoc analysis of participants in the ON-SXB group experiencing ≥5% weight loss (weight-loss group) was conducted. Results In REST-ON (n=212), mean participant age was 31.2 years (range, 16–72), 67.9% were female, 75.5% were white, 76.4% had NT1, mean baseline BMI was 28.1 kg/m2 (range, 16.9–71.9), and 61.3% were taking stimulants. At week 13, 17.8% (19/107) of participants receiving ON-SXB experienced ≥5% weight loss vs 3.8% (4/105) of participants receiving placebo (P< 0.001). Compared to the REST-ON population, the weight-loss group had similar age and proportion of NT1 diagnosis, a smaller proportion was female, and a higher proportion was white and was taking stimulants. At baseline, mean BMI was 25.6 kg/m2 (range, 20.3–34.0) in the weight-loss group, 47.4% (9/19) were overweight (BMI 25.0–29.9 kg/m2) or obese (BMI >30 kg/m2); none were underweight (BMI < 18.5 kg/m2). At week 13, 31.6% (6/19) remained overweight or obese; none were underweight. Excessive daytime sleepiness was significantly improved from baseline to week 13 (ON-SXB 9 g) in the weight-loss group vs the ON-SXB group without weight loss (Maintenance of Wakefulness test, P< 0.05; Epworth Sleepiness Scale score, P< 0.001). Adverse events of nausea and vomiting were more frequent in the weight-loss group vs the ON-SXB group without weight loss; however, rate of discontinuations owing to AEs in the weight-loss group was approximately half that of the ON-SXB group without weight loss. Conclusion These data expand the body of knowledge regarding weight loss during treatment with sodium oxybate. Given the high proportion of comorbid obesity among people with narcolepsy, the additional benefit of potential weight loss with sodium oxybate may further inform treatment selection. Whereas ON-SXB was effective overall, further exploration of possible increased pharmacologic response in certain subgroups should be evaluated. Support (if any) Avadel Pharmaceuticals

Correction of Psychoemotional Disorders and Short-Term Prognosis in Patients with COVID-19.

This review discusses the importance of the main psychoemotional risk factors for the development of chronic noncommunicable diseases. Current data on the prevalence of anxiety and depressive disorders in patients with cardiovascular disease (CVD) are presented. Data on the relationship between the development of psychoemotional disorders and CVD are summarized and the prospects for managing such patients within the framework of interdisciplinary cooperation are discussed. The main pathogenetic mechanisms for the development of complications, including CNS damage in COVID-19, are considered. The significance of the selection of pathogenetic therapy for patients with comorbid somatic and mental diseases in the context of the COVID-19 pandemic is discussed. Results from multicenter placebo-controlled studies of the use of fluvoxamine in patients with COVID-19 of varying severity are addressed.

A Phase 3 Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of AB-205 Plus Standard of Care (SOC) Versus Placebo Plus Standard of Care in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (E-CELERATE) (NCT05181540) - Trials in Progress

Myeloablative conditioning or high-dose therapy followed by autologous hematopoietic cell transplantation (HDT-AHCT) is a standard of care (SOC) and potentially curative consolidation therapy for eligible patients diagnosed with aggressive lymphoma. Although effective in chemosensitive patients, HDT-AHCT is associated with severe regimen-related toxicities (SRRTs) that affect quality of life and may increase mortality risk (Olivieri et al., BBMT 2018). SRRTs occur due to the off-target cytotoxicity of HDT that involves damage to the microvasculature and the vascular stem cell niches of multiple organs. SRRTs predominantly affect organs with high cell turnover causing severe complications such as diffuse gastrointestinal (GI) mucositis (oral/GI SRRT) and delayed hematopoietic recovery. Rates and severity of toxicities increase with age, relevant to the demographics of the aging lymphoma population. Importantly, patients identify oral/GI SRRT as one of the most severe adverse effects experienced with HDT-AHCT (Stiff et al., BMT 2001). Notwithstanding, there are limited treatment strategies aimed at preventing SRRTs. AB-205 is an experimental, engineered cell therapy that consists of allogeneic, human umbilical vein endothelial cells transduced with the pro-survival E4ORF1+ gene (E-CEL® cells). The proposed mechanism of action is paracrine in nature consisting of cell expression of reparative angiocrine factors which are thought to accelerate the repair injuries from off-target cytotoxicity of myeloablative conditioning. In a previously presented Phase 1/2 study [NCT03925935] in HCT-eligible patients with lymphoma, AB-205 was well tolerated and resulted in a 9% incidence of early oral/GI SRRT [defined as Grade ≥3 mucositis (M), nausea (N), vomiting (V) or diarrhea (D) in systemic lymphoma subjects conditioned with BEAM and BEAM-alternates (Phase 1/2 data is locked and analysis is in progress). This oral/GI SRRT incidence compared highly favorably to an incidence rate of 41% resulting from a contemporary, retrospective observational study conducted at two phase 1/2 sites (done concurrently during the conduct of the phase 1/2 study). Accordingly, a phase 3, randomized, double-blind, placebo-controlled multi-center study (E-CELERATE) has been initiated to further investigate the efficacy and safety of AB-205 in reducing (preventing) severe toxicities and complications related to off-target cytotoxicity of myeloablative HDT. Approximately 140 patients will be enrolled across 25 sites in the United States. Key inclusion criteria: Age ≥ 40; diagnosis of Hodgkin or non-Hodgkin lymphoma who are candidates for HDT-AHCT with one of the following myeloablative conditioning regimens: carmustine, etoposide, cytarabine, melphalan (BEAM); bendamustine, etoposide, cytarabine, melphalan (BeEAM); achieved complete response (CR) or partial response (PR) prior to planned HDT; ECOG ≤ 2; serum bilirubin ≤ 2 mg/dL; AST, ALT, and alkaline phosphatase < 3 × ULN. Key exclusion criteria: Prior HCT; primary CNS lymphoma; systemic lymphoma with secondary CNS involvement at time of relapse prior to planned HDT-AHCT; active malignancy other than the one for which the subject is undergoing HDT-AHCT; subjects with a known history of HIV. Endpoints: The primary endpoint is complete response defined as the absence of oral/GI SRRT (NCI CTCAE Grade ≥ 3 M, N, V, or D from the time of HDT through Day +21 post-HCT). Secondary endpoints include the duration of oral/GI SRRT; patient-reported symptom burden per MD Anderson Symptom Inventory; duration of febrile neutropenia; time to neutrophil engraftment; incidence of Grade ≥ 3 non-hematologic treatment emergent AEs; absence of SRRT; and survival endpoints: non-relapse mortality, progression free survival and overall survival. Eligible patients will be randomized 1:1 to receive SOC supportive care prophylaxis + AB-205 or placebo intravenously (IV) given on Day 0 within 4 hours of AHCT. 20×106 cells/kg AB-205 IV or an analogous volume of placebo IV will be administered. Randomization will be stratified by lymphoma type (HL/NHL), hematopoietic cell transplantation-comorbidity index, disease status prior to HDT (CR/PR). Daily assessments of oral/GI SRRT will occur from start of HDT to Day +21 post AHCT (Figure 1). Current status: Active recruitment and enrollment ongoing [NCT05181540]. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Fast pain relief in exercise-induced acute musculoskeletal pain by turmeric-boswellia formulation: A randomized placebo-controlled double-blinded multicentre study.

Background:Plant extracts with analgesic properties are seldom considered for treatment of acute musculoskeletal pain due to delay in onset of analgesia. Turmeric (Curcuma longa) and boswellia (Boswellia serrata) extracts are well-studied anti-inflammatory compounds gaining in popularity and used as an alternative to conventional treatments for musculoskeletal pain. This study analyzed the analgesic effect of a formulation of turmeric and boswellia extracts in sesame oil (Rhuleave-K, TBF) in reducing exercise-induced acute musculoskeletal pain in healthy participants.Methods:In this randomized double-blinded placebo-controlled, single-dose, single-day, multicentre study, a total of 232 participants (TBF n = 116; placebo n = 116) having moderate-to-severe exercise-induced acute musculoskeletal pain were randomized in an allocation concealed 1:1 ratio to receive a single dose of 1000 mg of TBF or placebo. The outcome measures were numerical rating scale (NRS), categorical pain relief scale (PRS), onset of analgesia, and short form of McGill questionnaire (SF-MPQ). NRS and PRS were measured from predose to every 30 minutes interval of postdose up to 6 hours at rest, with movement and applying pressure on the affected part. The onset of analgesia was measured from the time of dosage and censored at 6 hours of postdose. The sum of pain intensity difference (SPID6) and total pain relief (TOTPAR6) at 6 hours was, respectively, analyzed from NRS and PRS scores.Results:TBF showed a significant reduction in pain intensity (SPID6rest) with 97.85% improvement in cumulative responder analysis compared with 2.46% in placebo. The onset of pain relief was fast and highly significant in the TBF group with 99% of participants having a mean perceptible pain relief at 68.5 minutes (95% confidence interval, 59.5–77.4) and 96% of participants having a mean meaningful pain relief at 191.6 minutes (95% confidence interval, 176.7–206.4) compared to the placebo group. Highly significant and continuous improvement in pain relief was observed in the TBF group with 93% of participants having ≥ 50% of maximum TOTPAR6 with a number needed to treat of 1.1 at rest.Conclusion:Exercise-induced acute musculoskeletal pain can be effectively relieved by TBF (Rhuleave-K) in about 3 hours signifying its strong analgesic activity.

Sodium Butyrate Effectiveness in Children and Adolescents with Newly Diagnosed Inflammatory Bowel Diseases-Randomized Placebo-Controlled Multicenter Trial.

Background: Butyric acid’s effectiveness has not yet been assessed in the pediatric inflammatory bowel disease (IBD) population. This study aimed to evaluate the effectiveness of oral sodium butyrate as an add-on to standard therapy in children and adolescents with newly diagnosed IBD. Methods: This was a prospective, randomized, placebo-controlled multicenter study. Patients aged 6–18 years with colonic Crohn’s disease or ulcerative colitis, who received standard therapy depending on the disease’s severity, were randomized to receive 150 mg sodium butyrate twice a day (group A) or placebo (group B). The primary outcome was the difference in disease activity and fecal calprotectin concentration between the two study groups measured at 12 weeks of the study. Results: In total, 72 patients with initially active disease completed the study, 29 patients in group A and 43 in group B. At week 12 of the study, the majority of patients achieved remission. No difference in remission rate or median disease activity was found between the two groups (p = 0.37 and 0.31, respectively). None of the patients reported adverse events. Conclusions: A 12-week supplementation with sodium butyrate, as adjunctive therapy, did not show efficacy in newly diagnosed children and adolescents with IBD.

Muscarinic-3-receptor positive allosteric modulator ASP8302 in patients with underactive bladder. A randomized controlled trial.

The aim of this study is to evaluate safety and efficacy of ASP8302, a novel positive allosteric modulator for the muscarinic M3 receptor (M3-PAM), in patients with underactive bladder (UAB). A randomized, double-blind, placebo-controlled multicenter study was performed in adult male/female subjects with UAB, defined as incomplete bladder emptying (postvoid residual volume [PVR] > 100 ml) without significant bladder outlet obstruction and/or overactive bladder. Subjects were randomized (1:1) to receive 4-week oral once-daily administration of 100 mg ASP8302 or matching placebo. Primary endpoint was a change from baseline in PVR measured by catheterization after standardized bladder filling (PVRC2 ). Other endpoints included PVR and bladder voiding efficiency (BVE) measured in various ways, uroflowmetry, bladder diary, and questionnaires. Pressure-flow studies were performed in a subgroup. One hundred and thirty-five patients were randomized (ASP8302 group: 65 patients, placebo group: 70 patients). The median change in PVRC2 was -40.0 ml (ASP8302) versus -35.0 ml (placebo) and the difference between groups was -5.0 ml (p = 0.960). In males, functional and symptomatic outcomes improved, for example, maximum urine flow rate (Qmax ) and detrusor pressure at Qmax (Pdet.Qmax ) increased (mean difference in change ASP8302 vs. placebo: 3.8 ml/s, p = 0.031 and 12.7 cm H2 O, p = 0.034, respectively). Urinary incontinence episodes/24 h decreased in males with preexisting incontinence (mean difference: -0.35; p = 0.028). The incidence of adverse events was similar between study groups (ASP8302: 33.3%, placebo: 31.4%). In the included subjects, both baseline urine flow and bladder voiding pressure was low. Compared with PVR, simultaneous BVE measurements were more consistent between various methods (spontaneous vs. standardized bladder filling, catheterization vs. ultrasound [US]). ASP8302 was safe and well tolerated in patients with UAB identified by nonurodynamic clinical criteria, but it did not show efficacy in the primary endpoint. However, in males it showed improvement of symptoms and functional parameters. BVE (using US) is a more optimal outcome measure than PVR in UAB.

Correction of psychoemotional disorders and short-term prognosis in patients with COVID-19

This review discusses the importance of the main psychosocial risk factors in the development of chronic non-communicable diseases. The current data on the prevalence of anxiety and depressive disorders in patients with cardiovascular diseases (CVD) are presented. The article summarizes information about the relationship between the development of psychoemotional disorders and CVD, discusses the prospects for the management of such patients in the framework of interdisciplinary cooperation. The main pathogenetic mechanisms of the development of complications, including damage to the central nervous system during infection with a new coronavirus infection, are considered. The significance of the choice of pathogenetic therapy for patients with comorbid somatic and mental diseases in the conditions of a pandemic of a new coronavirus infection is assessed. The results of multicenter placebo-controlled studies on the use of fluvoxamine in patients with a new coronavirus infection of varying severity are discussed.

Meta-analysis and randomized controlled studies: what clinicists should know to prevent regular and spontaneous miscarriages of unexplained genesis?

The etiopathology of recurrent miscarriage is a combination of various factors, including chromosomal defects, genetic or structural abnormalities, endocrine abnormalities, infections, immune dysfunction, thrombophilia disorders, antiphospholipid syndrome, and unexplained causes.It has long been known that progesterone is needed to maintain pregnancy and its physiological development. Insufficient progesterone secretion and its low level in the blood serum in early pregnancy is associated with the threat of miscarriage and loss of pregnancy at a later stage – up to 16 weeks of gestation. The effectiveness of the vaginal micronized progesterone (VMP) at a dose of 400 mg twice a day in the first trimester of pregnancy was evaluated in two recent large high-quality multicenter placebo-controlled studies, one of which included pregnant women with recurrent miscarriages of unexplained origin (PROMISE Trial), and the other study included women with early pregnancy loss (PRISM Trial). A key finding, pioneered in the PROMISE study and later confirmed in the PRISM study, was that VMP treatment associated with an increase in live births in line with the number of previous miscarriages. It has been shown that there is no evidence regarding safety concerns with natural micronized progesterone. Treatment with an VMP should be recommended for women with bleeding in early pregnancy and a history of one or more miscarriages. The recommended treatment regimen is 400 mg 2 times a day (800 mg/day) intravaginal, starting from the moment bleeding is detected up to 16 weeks of pregnancy.In the future, there remains uncertainty effectiveness and safety of alternative progestogens (dydrogesterone) for the treatment of women at high risk of threatened abortion and recurrent miscarriage. It is important that dydrogesterone is a synthetic progestin, its structure is significantly different from natural progesterone, and therefore it is necessary to unequivocally prove the short- and long-term safety of this drug before considering its use in clinical practice.

Efficacy and Safety of the Cudrania tricuspidata Extract on Functional Dyspepsia: A Randomized Double-Blind Placebo-Controlled Multicenter Study.

Cudrania tricuspidata is a folk remedy used to treat inflammation in patients with tumors or liver damage. This study investigated the efficacy of Cudrania tricuspidata extract (CTE) for relieving the symptoms of functional dyspepsia. In an 8-week, randomized, double-blind, placebo-controlled study, 100 adults with any condition featured in the Rome IV criteria and a Gastrointestinal Symptoms Scale (GIS) score ≥4 were randomly allocated to take either a placebo (maltodextrin) or a 50 mg CTE tablet, which equally included celluloses, magnesium stearate, and silicon dioxide, twice daily, 20 January 2020, and 3 August 2020. Among the 83 participants finally analyzed, the CTE group was associated with a significant reduction in the gastrointestinal symptom rating scale (day 0: 8.0 ± 5.2, day 28: 4.7 ± 3.9, and day 56: 2.3 ± 2.4, p < 0.001, respectively) in comparison with the control group (day 0: 8.1 ± 4.7, day 28: 7.8 ± 5.7, and day 56: 7.5 ± 6.6, p > 0.05) after adjusting for smoking, drinking, eating habits, stress levels, and caffeine intake. The CTE group resulted in significant improvements of GIS, Nepean Dyspepsia Index (Korean version), and functional dyspepsia-related quality of life over time. There were no different adverse events (p = 0.523). These findings suggest that CTE is safe and efficacious for alleviating gastrointestinal symptoms in patients with functional dyspepsia.

Mifepristone and misoprostol versus placebo and misoprostol for resolution of miscarriage in women diagnosed with missed miscarriage: the MifeMiso RCT.

A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne®, Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage. Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1 : 1 ratio) to receive 200 mg of oral mifepristone or matched placebo, followed by 800 μg of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage. A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p = 0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p = 0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of £182 (95% confidence interval £26 to £338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage. Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage. Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone. Current Controlled Trials ISRCTN17405024. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 68. See the NIHR Journals Library website for further project information.

A randomized, double-blind, placebo-controlled, multicenter study assessing the efficacy of magnesium oxide monohydrate in the treatment of nocturnal leg cramps

BackgroundMagnesium supplements are widely used for prophylaxis and treatment of nocturnal leg cramps (NLC). However, there is little evidence in support of their effectiveness. The main impediment stems from the lack of assessments of cellular absorption. In the current study, we tested the efficacy and safety of a magnesium supplement – magnesium oxide monohydrate (MOMH), for which increased cellular absorption rates were demonstrated in an ex-vivo setting.MethodsA randomized, double-blind, placebo-controlled multicenter study was conducted in hospitals and outpatient clinics in Ukraine, from February to August 2018. Eligible subjects received a capsule with MOMH 226 mg or placebo, once daily, at bedtime, for a 60-day period. The assessed parameters included frequency and duration of NLC episodes, quality of sleep, NLC-induced pain and quality of life sub-scores. The Fisher’s Exact Test for comparison of groups by categorical variables was used. The Student’s test or Mann-Whitney test were used for between-group comparison at different timepoints. ANCOVA followed by contrast analysis was used for comparison of groups at the end of the study.Results175 (81%) out of 216 initially screened subjects completed the study. The number of NLC episodes has significantly decreased by the end of the study period as compared to baseline in both groups (p < 0.001 for both). There was a significant between-group difference in the magnitude of reduction in NLC episodes (p = 0.01), indicating a higher decrease in the MOMH group as compared to the placebo group (− 3.4 vs − 2.6, respectively). In addition, MOMH treatment resulted in a greater reduction in NLC duration (p < 0.007) and greater improvement in sleep quality (p < 0.001) as compared to placebo.ConclusionsMOMH was shown to be effective in the treatment of NLC as well as safe and well-tolerated.Trial registrationNCT03807219, retrospectively registered on January 16, 2019.

Changes in Serum Cytokines Throughout Pregnancy in Women With Polycystic Ovary Syndrome.

ContextPolycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade inflammation and increased incidence of pregnancy complications, but its influence on the maternal immune system in pregnancy is unknown. Longitudinal serum cytokine profiling is a sensitive measure of the complex immunological dynamics of pregnancy.ObjectiveThis work aimed to determine the immunological dynamics of serum cytokines throughout pregnancy in women with PCOS and compare it to pregnancy in women without PCOS.MethodsA post hoc analysis was conducted of longitudinal serum samples from 2 randomized, placebo-controlled multicenter studies of pregnant women with PCOS and 2 studies of pregnant women without PCOS. Pregnant women with PCOS (n = 358) and without PCOS (n = 258, controls) provided 1752 serum samples from 4 time points in pregnancy (weeks 10, 19, 32, and 36). Main outcome measures included maternal serum levels of 22 cytokines and C-reactive protein (CRP) at 4 time points in pregnancy.ResultsWomen with PCOS showed marked immunological changes in serum cytokines throughout pregnancy. Compared to controls, women with PCOS showed higher levels of 17 cytokines and CRP at week 10 of pregnancy and a distinct cytokine development throughout pregnancy. The immunological dynamics in women with PCOS was significantly affected by maternal body mass index, smoking, and fetal sex.ConclusionPregnancy in women with PCOS was associated with a strong early mobilization of inflammatory and other serum cytokines persisting throughout pregnancy, indicating a more activated immune status. These findings provide a novel basis for further study of PCOS and pregnancy complications.

The Effectiveness of Cobalamin (B12) Treatment for Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder affecting 2% of children in the United States. Biochemical abnormalities associated with ASD include impaired methylation and sulphation capacities along with low glutathione (GSH) redox capacity. Potential treatments for these abnormalities include cobalamin (B12). This systematic review collates the studies using B12 as a treatment in ASD. A total of 17 studies were identified; 4 were double-blind, placebo-controlled studies (2 examined B12 injections alone and 2 used B12 in an oral multivitamin); 1 was a prospective controlled study; 6 were prospective, uncontrolled studies, and 6 were retrospective (case series and reports). Most studies (83%) used oral or injected methylcobalamin (mB12), while the remaining studies did not specify the type of B12 used. Studies using subcutaneous mB12 injections (including 2 placebo-controlled studies) used a 64.5–75 µg/kg/dose. One study reported anemia in 2 ASD children with injected cyanocobalamin that resolved with switching to injected mB12. Two studies reported improvements in markers of mitochondrial metabolism. A meta-analysis of methylation metabolites demonstrated decreased S-adenosylhomocysteine (SAH), and increased methionine, S-adenosylmethionine (SAM), SAM/SAH ratio, and homocysteine (with small effect sizes) with mB12. Meta-analysis of the transsulfuration and redox metabolism metabolites demonstrated significant improvements with mB12 in oxidized glutathione (GSSG), cysteine, total glutathione (GSH), and total GSH/GSSG redox ratio with medium to large effect sizes. Improvements in methylation capacity and GSH redox ratio were significantly associated with clinical improvements (with a mean moderate effect size of 0.59) in core and associated ASD symptoms, including expressive communication, personal and domestic daily living skills, and interpersonal, play-leisure, and coping social skills, suggesting these biomarkers may predict response to B12. Other clinical improvements observed with B12 included sleep, gastrointestinal symptoms, hyperactivity, tantrums, nonverbal intellectual quotient, vision, eye contact, echolalia, stereotypy, anemia, and nocturnal enuresis. Adverse events identified by meta-analysis included hyperactivity (11.9%), irritability (3.4%), trouble sleeping (7.6%), aggression (1.8%), and worsening behaviors (7.7%) but were generally few, mild, not serious, and not significantly different compared to placebo. In one study, 78% of parents desired to continue mB12 injections after the study conclusion. Preliminary clinical evidence suggests that B12, particularly subcutaneously injected mB12, improves metabolic abnormalities in ASD along with clinical symptoms. Further large multicenter placebo-controlled studies are needed to confirm these data. B12 is a promising treatment for ASD.

Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D)

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

A randomized, Double-Blind, Placebo-Controlled Multicenter Study of Kan Jang® Capsules in Patients with URTI Infection with the Primary Outcome of Sick Leave Days

In this study, we also found that the sick leave for the placebo group was 1.79 days, while the sick leave in the Kan Jang group was reduced to 0.44 days.

Effect of Eurycoma longifolia standardised aqueous root extract–Physta® on testosterone levels and quality of life in ageing male subjects: a randomised, double-blind, placebo-controlled multicentre study

BackgroundLow testosterone levels cause physiological changes that compromise the quality of life in ageing men. A standardised water extract from the root of Eurycoma longifolia (EL), known as Physta®, is known to increase testosterone levels.ObjectiveTo evaluate the safety and efficacy of Physta® in improving the testosterone levels and quality of life in ageing male subjects.DesignThis randomised, double-blind, placebo-controlled study enrolled 105 male subjects aged 50–70 years with a testosterone level <300 ng/dL, BMI ≥ 18 and ≤30.0 kg/m2. The subjects were given either Physta® 100 mg, 200 mg or placebo daily for 12 weeks. The primary endpoints were changes in serum total and free testosterone levels. The secondary endpoints included changes in the level of sex hormone-binding globulin (SHBG), dihydroepiandrosterone (DHEA), glycated haemoglobin (HbA1c), insulin-like growth factor-1 (IGF-1), thyroid function tests (T3, T4, TSH and Free T3) and cortisol. Changes in Ageing Male Symptoms (AMS) score, Fatigue Severity Scale (FSS) score and muscle strength are other secondary endpoints. The safety of the intervention products was measured by complete blood count, lipid profile, liver and renal function tests.ResultsThere was a significant increase in the total testosterone levels at week 12 (P < 0.05) in the Physta® 100 mg group and at weeks 4 (P < 0.05), 8 (P < 0.01) and 12 (P < 0.001) in the Physta® 200 mg group compared to placebo. No significant between-group differences in free testosterone levels were observed but a significant within-group increase occurred at weeks 4 (P < 0.01), 8 (P < 0.001) and 12 (P < 0.001) in the Physta®100 mg group and at weeks 2 (P < 0.01), 4 (P < 0.01), 8 (P < 0.001) and 12 (P < 0.001) in the Physta® 200 mg group. The AMS and FSS showed significant reduction (P < 0.001) in total scores at all time-points within- and between-group in both Physta® groups. DHEA levels significantly increased (P < 0.05) within-group in both Physta® groups from week 2 onwards. Cortisol levels significantly (P < 0.01) decreased in the Physta® 200 mg group, while muscle strength significantly (P < 0.001) increased in both Physta® groups at week 12 in the within-group comparison. There were no significant changes in SHBG. No safety related clinically relevant changes were observed.ConclusionSupplementation of Physta® at 200 mg was able to increase the serum total testosterone, reduce fatigue and improve the quality of life in ageing men within 2 weeks’ time.Trial registrationThis clinical study has been registered in ctri.nic.in (CTRI/2019/03/017959).