Placebo-controlled Randomized Controlled Trials Research Articles

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative.

Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications. We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication. Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation. Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.

Adverse Effects of Low-Dose Methotrexate in a Randomized Double-Blind Placebo-Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial.

ObjectiveLow‐dose methotrexate (LD‐MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD‐MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD‐MTX versus placebo in a large randomized controlled trial (RCT).MethodsWe prespecified secondary analyses of a double‐blind, placebo‐controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada. Subjects were randomly allocated to LD‐MTX (20 mg/week maximum) or placebo. All subjects received folic acid (1 mg daily for 6days/week). We assessed the frequency of blindly adjudicated hematologic and malignant adverse events (AEs).ResultsA total of 2391 subjects were randomized to LD‐MTX (mean dosage 14.9 mg/week), and 2395 were randomized to placebo. During follow‐up, in the LD‐MTX arm, simultaneous two‐line cytopenias (n = 92 [3.9%]) or pancytopenia (n = 13 [0.54%]) were infrequent. Pancytopenia developed as soon as 4 months and as late as 3.5 years after beginning LD‐MTX, though the latter subject had been recently diagnosed with multiple myeloma. Overall skin cancer risk was increased in users of LD‐MTX compared with users of placebo, which driven largely by a statistically significant increased risk of squamous cell skin cancer (hazard ratio [HR] 3.31; 95% confidence interval [CI] 1.63‐6.71). Melanoma was increased in LD‐MTX, but this was not statistically significant (HR 2.33; 95% CI 0.60‐9.01).ConclusionsAmong subjects using LD‐MTX, simultaneous two‐line cytopenias and pancytopenia were uncommon. We found more cases of skin cancer, particularly squamous cell carcinomas, in the LD‐MTX arm than the placebo arm.

Corticosteroid therapy for nephrotic syndrome in children.

Corticosteroid therapy for nephrotic syndrome in children.

Individual response to antidepressants for depression in adults-a meta-analysis and simulation study.

The observation that some patients appear to respond better to antidepressants for depression than others encourages the assumption that the effect of antidepressants differs between individuals and that treatment can be personalized. To compare the outcome variance in patients receiving antidepressants with the outcome variance in patients receiving placebo in randomized controlled trials (RCTs) of adults with major depressive disorder (MDD) and to illustrate, using simulated data, components of variation of RCTs. From a dataset comprising 522 RCTs of antidepressants for adult MDD, we selected the placebo-controlled RCTs reporting outcomes on the 17 or 21 item Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale and extracted the means and SDs of raw endpoint scores or baseline to endpoint changes scores on eligible depression symptom rating scales. We conducted inverse variance random-effects meta-analysis with the variability ratio (VR), the ratio between the outcome variance in the group of patients receiving antidepressants and the outcome variance in the group receiving placebo, as the primary outcome. An increased variance in the antidepressant group would indicate individual differences in response to antidepressants. We analysed 222 RCTs that investigated 19 different antidepressants compared with placebo in 345 comparisons, comprising a total of 61144 adults with an MDD diagnosis. Across all comparisons, the VR for raw endpoint scores was 0.98 (95% CI 0.96 to 1.00, I2 = 0%) and 1.00 (95% CI 0.99 to 1.02, I2 = 0%) for baseline-to-endpoint change scores. Based on these data, we cannot reject the null hypothesis of equal variances in the antidepressant group and the placebo group. Given that RCTs cannot provide direct evidence for individual treatment effects, it may be most reasonable to assume that the average effect of antidepressants applies also to the individual patient.

The Safety of Laser Acupuncture: A Systematic Review

Objective: Laser acupuncture has become increasingly attractive in clinical practice, especially for patients with needle phobias well as elderly people and children. However, literature concerning the safety of laser acupuncture has been limited. This systematic review synthesizes the current available literature on the safety of laser acupuncture.Methods: Ovid MEDLINE,® Epub Ahead of Print, In-Process & Other Non-Indexed Citations Daily, Ovid Embase, Scopus, and EBM Reviews—Cochrane Central Register of Controlled Trials databases were searched for available randomized controlled trials (RCTs) on laser acupuncture. Safety data were extracted from the included studies. Adverse events (AEs) data were extracted and assessed in terms of severity and causality.Results: Of 737 articles, 21 RCTs were included. The majority of these RCTs reported that laser acupuncture was safe, without AEs; 6 trials reported AEs (including tingling, pain flare-ups, and transient fatigue). All AEs were mild and resolved spontaneously within 24 hours. The causal relationship between AEs and laser acupuncture was felt to be “certain” in 4 studies, “probable” in 1 study, and “possible” in 1 study. AEs were collected and monitored by evaluation methods in 7 trials: 5 with AE questionnaires, 1 with a checklist, and 1 with oral reports.Conclusions: Laser acupuncture appears to be a safe therapy associated with few mild and transient AEs. However, given the heterogeneity of current studies, large, well-designed placebo-controlled RCTs with rigorous evaluation methods are needed to assess the safety of laser acupuncture more completely.

The Use of Curcumin as a Complementary Therapy in Ulcerative Colitis: A Systematic Review of Randomized Controlled Clinical Trials.

The objective of this study was to systematically review the literature to verify the efficacy and safety of curcumin as a complementary therapy for the maintenance or induction of remission in patients with inflammatory bowel disease (IBD). A comprehensive search was conducted by two independent authors in MEDLINE (PubMed), Scopus, Web of Science, the Cochrane Library, Lilacs, Food Science and Technology s, and ScienceDirect. The search terms “curcumin”, “curcuma”, “inflammatory bowel disease”, “proctocolitis”, “crohn disease”, and “inflammation” were combined to create search protocols. This study considered randomized controlled trials (RCTs) published in any language before March 2020 that evaluated the effects of curcumin on inflammatory activity and the maintenance or remission of IBD patients. After duplicates were removed, 989 trials were identified, but only 11 met the eligibility criteria. Five of these were considered to be biased and were excluded. Therefore, six trials were considered in this review. All the studies included in the systematic review were placebo-controlled RCTs conducted on individuals with ulcerative colitis (UC). All the RCTs reported that curcumin was well tolerated and was not associated with any serious side effects. Studies show that curcumin may be a safe, effective therapy for maintaining remission in UC when administered with standard treatments. However, the same cannot be stated for Crohn’s disease due to the lack of low bias risk studies. Further studies with larger sample sizes are needed before curcumin can be recommended as a complementary therapy for UC.

VITamin D and OmegA-3 TriaL (VITAL): Effects of Vitamin D Supplements on Risk of Falls in the US Population.

ContextIt is unclear whether vitamin D supplementation reduces risk of falls, and results from randomized controlled trials (RCTs) are conflicting.ObjectiveThe objective of this work is to determine whether 2000 IU/day of supplemental vitamin D3 decreases fall risk.DesignVITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT including 25 871 adults, randomly assigned November 2011 to March 2014 and treated for 5.3 years (median).SettingThis is a nationwide study.ParticipantsMen 50 years or older and women 55 years or older (mean age, 67.1 years) without cancer or cardiovascular disease at baseline participated in this study.InterventionsInterventions included vitamin D3 (cholecalciferol; 2000 IU/day) and/or omega-3 fatty acids (1 g/day) or respective placebos in a 2 × 2 factorial design.Main Outcome MeasuresMain outcome measures include 2 or more falls and falls resulting in a doctor or hospital visit.ResultsBaseline serum total 25-hydroxyvitamin D (25[OH]D) level was 77 nmol/L; characteristics were well-balanced between groups. Numbers of participants with 2 or more falls were similar between active and placebo groups (9.8% vs 9.4%). Over 5 years, there were no differences in the proportion having 2 or more falls (odds ratio [OR] = 0.97; 95% CI, 0.90-1.05, P = .50), falls resulting in a doctor visit (OR = 1.03; 95% CI, 0.94-1.13, P = .46), or resulting in a hospital visit (OR = 1.04; 95% CI, 0.90-1.19, P = .61) between groups. Results did not differ between those with baseline 25(OH)D less than 50 vs 50 nmol/L or greater or other cut points.ConclusionDaily supplemental vitamin D3 vs placebo did not decrease fall risk in generally healthy adults not selected for vitamin D insufficiency. This large RCT does not indicate that supplemental vitamin D should be used for primary prevention of falls in the US population.

Clinical considerations for managing dermatology patients on systemic immunosuppressive or biologic therapy, or both, during the COVID-19 pandemic

Clinical considerations for managing dermatology patients on systemic immunosuppressive or biologic therapy, or both, during the COVID-19 pandemic

Adverse drug reactions associated with amitriptyline\xa0\u2014\xa0protocol for a systematic multiple-indication review and meta-analysis

BackgroundUnwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-the-counter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals.MethodsA systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including < 100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using meta-regression (for indication, outcome, and time points) and I2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment.DiscussionWe will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations.Systematic review registrationSubmitted to PROSPERO; assignment is in progress.

Pharmacological interventions for promoting smoking cessation during pregnancy.

Tobacco smoking in pregnancy causes serious health problems for the developing fetus and mother. When used by non-pregnant smokers, pharmacotherapies (nicotine replacement therapy (NRT), bupropion, and varenicline) are effective for increasing smoking cessation, however their efficacy and safety in pregnancy remains unknown. Electronic cigarettes (ECs) are becoming widely used, but their efficacy and safety when used for smoking cessation in pregnancy are also unknown.To determine the efficacy and safety of smoking cessation pharmacotherapies and ECs used during pregnancy for smoking cessation in later pregnancy and after childbirth, and to determine adherence to smoking cessation pharmacotherapies and ECs for smoking cessation during pregnancy.We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 May 2019), trial registers, and grey literature, and checked references of retrieved studies.Randomised controlled trials (RCTs) conducted in pregnant women, comparing smoking cessation pharmacotherapy or EC use with either placebo or no pharmacotherapy/EC control. We excluded quasi-randomised, cross-over, and within-participant designs, and RCTs with additional intervention components not matched between trial arms.We followed standard Cochrane methods. The primary efficacy outcome was smoking cessation in later pregnancy; safety was assessed by 11 outcomes (principally birth outcomes) that indicated neonatal and infant well-being. We also collated data on adherence to trial treatments. We calculated the risk ratio (RR) or mean difference (MD) and the 95% confidence intervals (CI) for each outcome for each study, where possible. We grouped eligible studies according to the type of comparison. We carried out meta-analyses where appropriate.We included 11 trials that enrolled a total of 2412 pregnant women who smoked at enrolment, nine trials of NRT and two trials of bupropion as adjuncts to behavioural support, with comparable behavioural support provided in the control arms. No trials investigated varenicline or ECs. We assessed four trials as at low risk of bias overall. The overall certainty of the evidence was low across outcomes and comparisons as assessed using GRADE, with reductions in confidence due to risk of bias, imprecision, and inconsistency. Compared to placebo and non-placebo (behavioural support only) controls, there was low-certainty evidence that NRT increased the likelihood of smoking abstinence in later pregnancy (RR 1.37, 95% CI 1.08 to 1.74; I² = 34%, 9 studies, 2336 women). However, in subgroup analysis by comparator type, there was a subgroup difference between placebo-controlled and non-placebo controlled RCTs (test for subgroup differences P = 0.008). There was unclear evidence of an effect in placebo-controlled RCTs (RR 1.21, 95% CI 0.95 to 1.55; I² = 0%, 6 studies, 2063 women), whereas non-placebo-controlled trials showed clearer evidence of a benefit (RR 8.55, 95% CI 2.05 to 35.71; I² = 0%, 3 studies, 273 women). An additional subgroup analysis in which studies were grouped by the type of NRT used found no difference in the effectiveness of NRT in those using patches or fast-acting NRT (test for subgroup differences P = 0.08). There was no evidence of a difference between NRT and control groups in rates of miscarriage, stillbirth, premature birth, birthweight, low birthweight, admissions to neonatal intensive care, caesarean section, congenital abnormalities, or neonatal death. In one study infants born to women who had been randomised to NRT had higher rates of 'survival without developmental impairment' at two years of age compared to the placebo group. Non-serious adverse effects observed with NRT included headache, nausea, and local reactions (e.g. skin irritation from patches or foul taste from gum), but data could not be pooled. Adherence to NRT treatment regimens was generally low. We identified low-certainty evidence that there was no difference in smoking abstinence rates observed in later pregnancy in women using bupropion when compared to placebo control (RR 0.74, 95% CI 0.21 to 2.64; I² = 0%, 2 studies, 76 women). Evidence investigating the safety outcomes of bupropion use was sparse, but the existing evidence showed no difference between the bupropion and control group.NRT used for smoking cessation in pregnancy may increase smoking cessation rates in late pregnancy. However, this evidence is of low certainty, as the effect was not evident when potentially biased, non-placebo-controlled RCTs were excluded from the analysis. Future studies may therefore change this conclusion. We found no evidence that NRT has either positive or negative impacts on birth outcomes; however, the evidence for some of these outcomes was also judged to be of low certainty due to imprecision and inconsistency. We found no evidence that bupropion may be an effective aid for smoking cessation during pregnancy, and there was little evidence evaluating its safety in this population. Further research evidence on the efficacy and safety of pharmacotherapy and EC use for smoking cessation in pregnancy is needed, ideally from placebo-controlled RCTs that achieve higher adherence rates and that monitor infants' outcomes into childhood. Future RCTs of NRT should investigate higher doses than those tested in the studies included in this review.

P416 Results of the first paediatric randomised controlled trial of faecal microbiota transplant for ulcerative colitis

Abstract Background The role of faecal microbiota transplant (FMT) for the treatment of ulcerative colitis (UC) has been reported across 4 randomised-controlled trials (RCT) in adults. Promising data have emerged from small, open-label paediatric case series and case reports but a proper blinded, placebo-controlled RCT has not been described in children. We report results from the first multicentre RCT of FMT in paediatric UC patients, conducted over 36 months in Ontario and Quebec, Canada. Methods We enrolled 25 children, ages 4–17 years old with active UC across two tertiary IBD clinics. Patients had active inflammation and remained on stable doses of medication at entry. Blinded participants received enemas containing healthy donor stool (active) or normal saline (placebo), 2×/week for 6 weeks. Faecal calprotectin (fCal), C-reactive protein (CRP), and paediatric ulcerative colitis activity index (PUCAI) scores were compared between groups during intervention, and at four follow-up time points over 30 weeks. Donor and recipient stools were measured for 16s rRNA and metagenomics analyses. Results In intention-to-treat (ITT) analysis, FMT (n = 13) at 6 weeks was more likely to improve clinical response (OR 9.3, 95% CI [0.7, 122.6]), CRP (OR 4.7, 95% CI [0.8, 28.4]), and fCal (OR 13.3, 95% CI [1.1, 166.4]) from baseline compared with placebo (n = 12). FMT at 30 weeks was also more likely than placebo to improve clinical response, CRP, and fCal (Table 1). In ITT analysis of the open-label arm (n = 7), FMT at 6 weeks and 30 weeks decreased CRP (−42.9%, −28.6%), fCal (−28.6%, −42.9%), and PUCAI score (−14.3%, −42.9%) from baseline. Conclusion Serial FMT enemas containing healthy donor microbiota led to greater improvements in serum and stool inflammatory markers, and rates of clinical response, in paediatric patients with active UC compared with placebo. These improvements largely persisted beyond 6 months after final FMT treatment. This study offers the strongest preliminary evidence, from a blinded, placebo-controlled multicentre RCT for the role of FMT in the management of paediatric UC.

Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL).

ABSTRACTAlthough supplemental vitamin D is used to promote bone health in the general population, data from randomized controlled trials (RCTs) have been inconsistent. We determined whether daily, vitamin D3 supplementation improves bone mineral density (BMD) and/or structure. VITamin D and OmegA‐3 TriaL (VITAL) is a double‐blind, placebo‐controlled RCT of supplemental vitamin D3 (2000 IU/d) and/or omega‐3 fatty acids (1 g/d) in 25,871 adults nationwide. This ancillary study included a subcohort of 771 participants (men ≥50 and women ≥55 years; not taking bone active medications) evaluated at baseline and at 2‐year follow‐up (89% retention). Total 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry (Quest Diagnostics, San Juan Capistrano, CA, USA). Free 25(OH)D (FVD) levels were measured using the ELISA assay by Future Diagnostics Solutions BV (Wijchen, Netherlands). Primary endpoints were 2‐year changes in areal (a) BMD at the spine, hip, and whole body determined by dual‐energy X‐ray absorptiometry (DXA). Secondary endpoints were 2‐year changes in volumetric (v) BMD and cortical thickness at the radius and tibia assessed by peripheral quantitative computed tomography. Supplemental vitamin D3 versus placebo had no effect on 2‐year changes in aBMD at the spine (0.33% versus 0.17%; p = 0.55), femoral neck (−0.27% versus −0.68%; p = 0.16), total hip (−0.76% versus −0.95%; p = 0.23), or whole body (−0.22% versus −0.15%; p = 0.60), or on measures of bone structure. Effects did not vary by sex, race/ethnicity, body mass index, or 25(OH)D levels. Among participants with baseline FVD levels below the median (<14.2 pmol/L), there was a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (−0.42% versus −0.98%; p = 0.044) with vitamin D3. Whether baseline FVD levels help to identify those more likely to benefit from supplementation warrants further study. Supplemental vitamin D3 versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials

AimThere are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease. MethodsWe systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH). Outcomes of interest included changes in serum liver enzyme levels, liver fat, liver fibrosis, or histologic resolution of NASH. ResultsWe included 29 RCTs involving a total of 2,617 individuals (∼45% had T2DM) that have used metformin (n=6 studies), glitazones (n=8 studies), glucagon-like peptide-1 receptor agonists (n=6 studies), dipeptidyl peptidase-4 inhibitors (n=4 studies) or sodium-glucose cotransporter-2 inhibitors (n=7 studies) to treat NAFLD. Although most anti-hyperglycaemic drugs improved serum liver enzyme levels, only glitazones (especially pioglitazone) and liraglutide showed an improvement of histologic features of NAFLD, with a mild beneficial effect also on liver fibrosis for pioglitazone only. ConclusionRCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with pioglitazone may warrant caution. Further well-designed RCTs are needed to better characterize the efficacy and safety of monotherapy and combination therapy with anti-hyperglycaemic agents in patients with NAFLD.

Herbal Medicine (Sihogayonggolmoryeo-Tang or Chai-Hu-Jia-Long-Gu-Mu-Li-Tang) for Treating Hypertension:A Systematic Review and Meta-Analysis.

Introduction For situations in which effective and safe natural-derived products to treat hypertension are needed, recent studies suggest that an herbal medicine, Sihogayonggolmoryeo-tang (SYM), can improve both hypertension and concurrent mood symptoms. We aimed to evaluate the effectiveness and safety of SYM in treating hypertension. Methods Thirteen English, Korean, and Chinese databases were comprehensively searched from their inception to May 2020. Randomized controlled trials (RCTs) using SYM as a monotherapy or adjunctive therapy for hypertension were evaluated. The primary outcome was the systolic and diastolic blood pressure (BP). Descriptive analyses of the relevant data were conducted, and where appropriate data were available, a meta-analysis was performed, and the results were presented as a risk ratio or mean difference with 95% confidence intervals. The risk of bias was assessed using the Cochrane risk of bias tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results Seven RCTs with 711 participants were included. Compared with placebo, SYM significantly lowered systolic and diastolic BP and concurrent depression. SYM significantly lowered systolic and diastolic BP compared with active controls; however, subgroup analysis revealed no differences between SYM and antihypertensives. In addition, SYM significantly decreased the level of concurrent depression compared with antidepressants. There was no consistent difference in BP reduction between SYM combined with antihypertensives and antihypertensives alone. No serious adverse events were reported following SYM administration. Most of the included studies had an unclear risk of bias, and the quality of evidence was generally rated “low.” Conclusion Current evidence suggests that SYM may have the potential to lower hypertension and concurrent depressive symptoms without serious adverse events. Additional high-quality, placebo-controlled RCTs should be conducted to confirm the efficacy of SYM.

The Effect of Bifidobacterium on Reducing Symptomatic Abdominal Pain in Patients with Irritable Bowel Syndrome: A Systematic Review

Probiotics, specifically Bifidobacteria, may improve abdominal pain in patients with irritable bowel syndrome (IBS); however, results from randomised controlled trials (RCTs) are conflicting. Here, we systematically reviewed the efficacy of Bifidobacteria on abdominal pain in IBS. We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register from inception to 20 May 2019, without language or date restrictions. The search strategy comprised of the combination of three concepts: supplementation, abdominal pain, and IBS. Inclusion criteria included double-blind placebo-controlled RCTs featuring Bifidobacteria supplementation in Rome-diagnosed IBS patients. A total of 8 RCTs involving a total of 1045 patients with Rome diagnosed IBS were included. The dose of total Bifidobacteria ranged from 106 to > 1011 cfu (colony-forming unit) and duration of supplementation ranged between 2 and 8 weeks. Bifidobacteria was delivered through either intake of fermented milk products, encapsulation or via a malted milk beverage, with all studies assessing abdominal pain via a visual analogue Likert scale. From the studies included, 50% (n = 4) of studies found a statistically significant improvement in abdominal pain following Bifidobacteria supplementation compared to placebo, 38% (n = 3) of studies found non-significant improvements and 12% (n = 1) showed a statistically significant dose-response effect of improvement. The evidence shows a heterogeneity of effect for Bifidobacteria dependent upon strain, dosage and delivery method. While not all studies demonstrate significant improvements in abdominal pain, none of the selected studies reported an increase in pain or other adverse effects.

Chinese medicine JQ granule combined with half-dose omeprazole for nonerosive reflux disease: A multicenter, randomized, double-blind, placebo-controlled trial study protocol

IntroductionNonerosive reflux disease (NERD) is a kind of esophageal disease manifesting mainly as heartburn and regurgitation. The prevalence of NERD in patients with gastroesophageal reflux disease is up to 70%, and it significantly affects the quality of life of patients. In China, besides proton-pump inhibitors (PPIs), a herbal formula is widely used in nonerosive reflux disease, which can improve intestinal and extra-intestinal symptoms of patients. This study will evaluate in a large, independent, randomized controlled trial (RCT) the comparative effectiveness of a specific type of Chinese herbal granule with half-dose PPI and full-dose PPI in managing nonerosive reflux disease. Methods and analysisThis trial will be a multicenter, randomized, double-blind, placebo-controlled RCT. A total of 204 participants will be enrolled and randomized (1:1) to each group: herb granules plus 10 mg omeprazole plus 10 mg dummy omeprazole; and dummy herb granules plus 20 mg omeprazole. The efficacy measures will be the changes in scores in the Gastroesophageal Reflux Disease Questionnaire, the Short-Form 36, the Patient Report Outcome, the 17-item Hamilton Depression Scale, and the Signs and Symptoms Scale. DiscussionThis study will focus on the quality control of a Chinese medical formulation. The RCT research procedure will be conducted under the supervision of the Good Clinical Practice (GCP) center. This trial will reduce the routine dosage of omeprazole while adding Jianpi Qinghua JQ granule, with the aim to discuss the safety and effectiveness of the Chinese herbal granule on esophageal and extraesophageal symptoms while meeting the ethical requirements.

The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta‐review of meta‐analyses of randomized controlled trials

The role of nutrition in mental health is becoming increasingly acknowledged. Along with dietary intake, nutrition can also be obtained from"nutrient supplements", such as polyunsaturated fatty acids (PUFAs), vitamins, minerals, antioxidants, amino acids and pre/probiotic supplements. Recently, a large number of meta-analyses have emerged examining nutrient supplements in the treatment of mental disorders. To produce a meta-review of this top-tier evidence, we identified, synthesized and appraised all meta-analyses of randomized controlled trials (RCTs) reporting on the efficacy and safety of nutrient supplements in common and severe mental disorders. Our systematic search identified 33 meta-analyses of placebo-controlled RCTs, with primary analyses including outcome data from 10,951 individuals. The strongest evidence was found for PUFAs (particularly as eicosapentaenoic acid) as an adjunctive treatment for depression. More nascent evidence suggested that PUFAs may also be beneficial for attention-deficit/hyperactivity disorder, whereas there was no evidence for schizophrenia. Folate-based supplements were widely researched as adjunctive treatments for depression and schizophrenia, with positive effects from RCTs of high-dose methylfolate in major depressive disorder. There was emergent evidence for N-acetylcysteine as a useful adjunctive treatment in mood disorders and schizophrenia. All nutrient supplements had good safety profiles, with no evidence of serious adverse effects or contraindications with psychiatric medications. In conclusion, clinicians should be informed of the nutrient supplements with established efficacy for certain conditions (such as eicosapentaenoic acid in depression), but also made aware of those currently lacking evidentiary support. Future research should aim to determine which individuals may benefit most from evidence-based supplements, to further elucidate the underlying mechanisms.

Effect of pravastatin treatment on circulating adiponectin: a meta-analysis of randomized controlled trials.

ObjectivePravastatin has been suggested to increase circulating adiponectin in humans. However, results of randomized controlled trials (RCTs) are inconsistent. We aimed to systematically evaluate the influence of pravastatin on circulating adiponectin in humans by performing a meta-analysis of RCTs.Materials and methodsStudies were identified via systematic searching of PubMed, Embase, and Cochrane’s Library databases. A random effect model was used to pool the results. Meta-regression and subgroup analyses were applied to explore the source of heterogeneity.ResultsEight RCTs with nine comparisons of 595 participants were included. Pravastatin treatment was associated with a significant increased level of circulating adiponectin as compared with controls (weighted mean difference [WMD] =0.63 µg/mL; 95% CI, 0.17–1.09 µg/mL; P=0.007) with moderate heterogeneity (I2=28%). These results were confirmed by meta-analysis of double-blinded placebo-controlled RCTs (WMD =0.82 µg/mL; P=0.01). Meta-regression analyses indicated that proportions of males in each study were positively correlated with the effect of pravastatin on adiponectin (coefficient: 0.015, P=0.03). Subgroup analyses confirmed that pravastatin significantly increased adiponectin in studies of males (WMD =1.41 µg/mL; P=0.008), but not in those of females (WMD =−0.04 µg/mL; P=0.94).ConclusionPravastatin treatment is associated with increased circulating adiponectin. Gender difference may exist regarding the effect of pravastatin treatment on adiponectin.

Efficacy of Oral Antibiotics for Non-Severe Exacerbations of Bronchiectasis in Children (BEST 1): A Multi-Centre, Double-Blind, Double-Dummy, Randomised Placebo-Controlled Trial

Background: Bronchiectasis guidelines recommend antibiotics for treating acute respiratory exacerbations, but placebo-controlled, randomised-controlled trials (RCTs) are lacking in children. Since many exacerbations are virus-triggered, antibiotics may be unnecessary for non-severe (non-hospitalised) episodes. We hypothesised that oral amoxicillin-clavulanate and azithromycin are both superior to placebo for achieving symptom resolution by day-14 when treating non-severe exacerbations in children. Methods: In this multicentre (n=4), parallel, double-dummy, double-blind, placebo-controlled three-arm RCT, children aged 1-19 years were randomised at exacerbation onset to receive: (a) amoxicillin-clavulanate (45mg/kg/day)/azithromycin-placebo, (b) azithromycin (5mg/kg/day)/amoxicillin-clavulanate-placebo, or (c) placebo/placebo for 14-days (Australian-New Zealand Registry, ACTRN12612000011886). The primary outcome was exacerbation resolution by day-14. Secondary outcomes included exacerbation duration, time-to-next exacerbation, parent cough-specific quality-of-life, laboratory and spirometry assessments and nasopharyngeal microbiology. Treatment arms were compared using generalised-linear-models. Statistical significance was set at p<0·0245. Findings: Between April 2012 and December 2017, 197 children were randomised (amoxicillin-clavulanate n=63, azithromycin n=67, placebo n=67). By day-14, exacerbations had resolved in 41 (65%), 41 (61%) and 29 (43%) children in the respective groups. Compared to placebo, the relative risk of resolution by day-14 for amoxicillin-clavulanate was 1·50 (95% confidence interval [CI] 1·08-2·09; p=0·02, number needed-to-treat-for-benefit=5, 95%CI 3-20) and for azithromycin 1·41 (95%CI 1·01-1·97; p=0·04). Compared to placebo, the median exacerbation duration was significantly shorter in the amoxicillin-clavulanate (7 versus 10-days, p=0·02), but not the azithromycin group (8 vs 10-days, p=0·24). Other secondary between-group outcomes were not significantly different. Azithromycin was associated with increased nasopharyngeal carriage of macrolide-resistant-bacteria, while respiratory viruses were identified in 53% of exacerbations. Interpretation: Amoxicillin-clavulanate and azithromycin both showed benefit compared to placebo for treating non-severe exacerbations of bronchiectasis in children. However, azithromycin was associated with increased carriage of antibiotic-resistant bacteria. Consequently, amoxicillin-clavulanate should remain the first-line oral antibiotic for treating non-severe exacerbations of bronchiectasis in children. Funding: This work was supported by the Australian National Health and Medical Research Council (NHMRC; project grant number 1019834,) the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children (1040830), and Cure Kids, Auckland, New Zealand (3702764/3539). VG was supported by an NHMRC post-graduate scholarship (1075119). ABC is supported by an NHMRC practitioner fellowship (1058213). KFO and HSV were supported by NHMRC CRE in Children’s Indigenous Lung Health fellowships (10450830). MB is supported by a NHMRC Hot North Fellowship (1131932). Declaration of Interest: We declare that we have no conflicts of interest. Ethical Approval: The protocol has received ethical approval from the respective Human Research Ethics Committees of all the participating institutions (Darwin: Department of Health and Families and Menzies School of Health Research; Brisbane: Children’s Health Services (Royal Children’s Hospital) and University of Queensland; Perth: Princess Margaret Hospital; Melbourne: Royal Children’s Hospital; Auckland: Northern Ethics Committee, Ministry of Health and Starship Children’s Health local ethics committee). The study is being conducted under Australia’s Therapeutic Goods Administration Clinical Trial Notification scheme.