Placebo-controlled Randomized Trial Research Articles

BlephEx-treatment for blepharitis: a prospective randomized placebo-controlled trial

Abstract Background Blepharitis is a chronic inflammatory condition of the eyelids that affects a large proportion of patients in eye care settings. First-line treatments provide only partial relief for many patients. The BlephEx™ device provides automated eyelid debridement and aims to remove pathogenic biofilms from the eyelid margin to treat blepharitis long-term. However, evidence supporting the efficacy of BlephEx™ is limited. Methods In this double-masked randomized controlled trial, 42 patients with symptomatic blepharitis refractory to treatment were assigned to the BlephEx™ treatment or sham treatment group. Outcome measures including Ocular surface disease index (OSDI), tear break-up time (TBUT), Schirmer test, and Efron grading scale scores were assessed at baseline and after 4 weeks. A crossover design in which the treatment groups were swapped after 4 weeks was used as a recruitment tool. After receiving treatment, two patients (one per group) were lost to follow-up. Results The sham group exhibited a significant decrease in the Efron Grading Scale score. No significant differences were observed in the other outcomes between the two groups. The BlephEx™ group showed slightly greater decreases in the OSDI and Efron grading scale scores and an increase in the TBUT than did the sham group, but these differences were not statistically significant. Mild discomfort was the most common side effect and occurred equally in both groups. Conclusions No significant difference in outcomes was observed between patients who underwent BlephEx™ therapy and those who received sham treatment. BlephEx™ treatment cannot be recommended for treating blepharitis. Trial registration Retrospectively registered on February 16, 2024 in the DRKS (German Clinical Trials Register under https://drks.de/search/de/trial/DRKS00033492) under the trial registration number DRKS00033492.

The efficacy and safety of dual orexin receptor antagonists in obstructive sleep apnea: A systematic review and meta-analysis of randomised controlled trials.

Dual orexin receptor antagonists (DORAs) are indicated for the treatment of insomnia disorder. However, DORAs may change sleep parameters, thus having adverse effects on patients with obstructive sleep apnea (OSA). This meta-analysis clarified the impact of DORAs in OSA treatment on sleep architecture and respiratory parameters. We systematically searched PubMed, Embase, and Cochrane Central databases for randomised control trials published up to May 2024. The search focussed on studies discussing the effects of DORAs on sleep architecture in patients with OSA. Nonrandomised studies were excluded. A meta-analysis using a random-effects model was performed. The patients were categorised into subgroups based on the treatment protocol (single or multiple dosages). The Cochrane risk of bias tool for randomised trials assessed the risk of bias. Our meta-analysis included four randomised placebo-controlled trials, encompassing 126 patients with a mean age of 49.1 years. The effects of DORAs on sleep architecture and respiratory parameters were examined. The main findings were as follows: DORAs significantly increased the total sleep time and improved sleep efficiency. However, they did not affect rapid eye movement sleep. DORAs also showed a trend towards decreased wake after sleep onset and did not increase the apnea-hypopnea index. DORAs did not increase the percentage of total sleep time with oxygen saturation lower than 90% and 85% compared with placebo, respectively. Furthermore, DORAs were not associated with significantly higher adverse effects compared with placebo. This meta-analysis demonstrated that DORAs improve sleep and do not impair nighttime respiratory function in patients with OSA.

No benefit from the addition of low-dose ketamine infusion to standard evidence-based care of patients with multiple rib fractures.

Multiple rib fractures from blunt thoracic trauma cause significant morbidity. Optimal current management includes multimodal analgesia, pulmonary hygiene, and early mobilization. Low-dose ketamine infusion (LDKI) has been proposed as an adjunctive analgesic in this setting. A prior study reported decreased pain scores with LDKI in patients with multiple rib fractures. We hypothesized that LDKI would decrease morphine milligram equivalents (MMEs) in patients with multiple rib fractures. A prospective randomized placebo-controlled trial was performed in adult (18 years or older) patients with three or more rib fractures. A prestudy power analysis calculated an 80% chance of identifying a 15% decrease in MMEs with 50 subjects. The study was approved by the institutional review board and informed consent obtained in all subjects. Demographic (age, sex) and injury specific information (Injury Severity Score, number of rib fractures) were obtained. Subjects were randomized 1:1 to receive continuous LDKI (0.1 mg/kg/h) or placebo infusion (0.9% NaCl) for ≤48 hours. All patients received a standard evidence-based multidisciplinary protocol for rib fractures management. Primary outcome measure was MME use or pulmonary complications. Statistical comparison of LDKI versus placebo was performed using the Mann-Whitney U test. All 50 enrolled subjects (placebo, 25; LDKI, 25) received study drug infusion. The two groups were well matched for age, Injury Severity Score, and number of rib fractures. We observed no differences in the Day 1 (p = 0.961), Day 2 (p = 0.373), or total MMEs (p = 0.946) between groups. Similar total MME use was observed when subjects who received ≥40 hours of study drug and were compared (p = 0.924). Use of LDKI did not alter subsequent need for opiate analgesics postinfusion, hospital length of stay, pulmonary complications, or need for readmission. The addition of LDKI to an established multimodal, evidence-based protocol for management of multiple rib fractures did not decrease opiate usage or impact pulmonary complications. Therapeutic/Care Managaement; Level I.

Design of a randomised controlled hybrid trial of nintedanib in patients with progressive myositis-associated interstitial lung disease.

The Myositis Interstitial Lung Disease Nintedanib Trial (MINT) is a hybrid trial, which is enrolling patients both at local sites and remotely via a decentralised site. The trial will investigate the efficacy and safety of nintedanib in patients with progressive myositis-associated interstitial lung disease (MA-ILD). MINT is an exploratory, prospective randomised placebo-controlled trial. Eligible patients will have myositis and evidence of fibrosing ILD on high-resolution computed tomography (HRCT), be taking standard of care medications for myositis, and meet criteria for ILD progression within the prior 24months based on decline in FVC, worsened fibrosis on HRCT, and/or worsened dyspnoea. Patients will be randomised 1:1 to receive nintedanib 150mg twice daily or placebo for 12weeks then open-label nintedanib for 12weeks. Patients will be enrolled at local sites and a decentralised site. Most study visits will be completed remotely using telemedicine or digital health technologies. The primary endpoint is the change in Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnoea domain score at week 12. Other endpoints include changes in other L-PF questionnaire domains, lung function, imaging, and physical activity, and assessment of adverse events. Data collected using remote versus clinic enrolment, and using home versus clinic spirometry, will be compared. MINT is an innovative, hybrid trial that will evaluate the effects of nintedanib on symptoms, quality of life, and ILD progression in patients with progressive MA-ILD and provide valuable information on the utility of decentralised recruitment and remote data collection in clinical trials. Clinicaltrials.gov NCT05799755 (date of registration: 05/04/2023).

Efficacy assessment of intravenous immunoglobulin for gastrointestinal involvement in systemic sclerosis using UCLA SCTC GIT: Case-based review.

To summarize the published evidence in the literature on the use of intravenous immunoglobulin in gastrointestinal tract involvement in systemic sclerosis patients and report the experience of our department. A systematic literature review was performed; and a literature search was conducted in MEDLINE and Embase until 1/5/2024, using the participants, intervention, comparator and outcomes framework. Only full-text articles involving systemic sclerosis adults, submitted to intravenous immunoglobulin (at least one administration) to treat primary gastrointestinal tract manifestations. The outcome was the University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 score to evaluate response to treatment. Two reviewers performed the assessment of data extraction and synthesis, independently. Four papers (two case reports and two retrospective studies) out of 35 references were included. In addition, we added two systemic sclerosis patients from our department in this review. In 25 systemic sclerosis patients, with various gastrointestinal tract manifestations, the intravenous immunoglobulin therapy was found to improve digestive tract symptoms in SSc patients, as shown by the decrease in the scores of University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0. No adverse events were reported, except for one case of low-grade fever post-administration. The results from this systematic literature review based on case series suggest that intravenous immunoglobulin may improve gastrointestinal tract symptoms assessed by the University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 scale, with only minor reported adverse events, suggestive of an acceptable safety profile. We believe that this systematic literature review will contribute to shed light on the efficacy and safety aspects of intravenous immunoglobulin treatment in the management of gastrointestinal tract symptoms; and multicenter randomized placebo-controlled trials are urgently needed to foster progress in this field.

Randomised control trial indicates micronutrient supplementation may support a more robust maternal microbiome for women with antenatal depression during pregnancy

Background and AimsWe investigated the effects of high dose dietary micronutrient supplementation or placebo on the human gut microbiome in pregnant women who had moderate symptoms of antenatal depression. There is a significant absence of well-controlled clinical studies that have investigated the dynamic changes of the microbiome during pregnancy and the relationship among diet, microbiome and antenatal depression. This research is among the first to provide an insight into this area of research. MethodsThis 12 - week study followed a standard double blinded randomised placebo-controlled trial (RCT) design with either high dose micronutrients or active placebo. Matching stool microbiome samples and mood data were obtained at baseline and post-treatment, from participants between 12 and 24 weeks gestation. Stool microbiome samples from 33 participants (17 in the placebo and 16 in the treatment group) were assessed using 16s rRNA sequencing. Data preparation and statistical analysis was predominantly performed using the QIIME2 bioinformatic software tools for 16s rRNA analysis. ResultsMicrobiome community structure became increasingly heterogenous with decreased diversity during the course of the study, which was represented by significant changes in alpha and beta diversity. This effect appeared to be mitigated by micronutrient administration. There were less substantial changes at the genus level, where Coprococcus decreased in relative abundance in response to micronutrient administration. We also observed that a higher abundance of Coprococcus and higher alpha diversity correlated with higher antenatal depression scores. ConclusionsMicronutrient treatment appeared to support a more diverse (alpha diversity) and stable (beta diversity) microbiome during pregnancy. This may aid in maintaining a more resilient or adaptable microbial community, which would help protect against decreases or fluctuations that are observed during pregnancy.

Nutraceutical interventions for erectile dysfunction: a systematic review and network meta-analysis.

Although nutraceutical-based treatments are often offered for erectile dysfunction (ED), their efficacy remains doubtful, and the choice of one substance over the other is challenged by the dearth of head-to-head comparative studies. We aimed to compare the efficacy of available nutraceutical interventions, alone or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in improving erectile function in men with ED through a network meta-analysis (NMA), which incorporates direct and indirect evidence into one model thus generating a hierarchy of effectiveness. PubMed, Scopus, Web of Sciences, and Cochrane Library databases were searched for randomized placebo-controlled trials (RCTs) assessing the effect of any nutraceutical regimen in improving erectile function when compared to each other, placebo, and/or PDE5i in men with ED. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). Two NMAs were also conducted separately for organic and non-organic ED. Reciprocal comparisons between all treatments were analyzed by league tables. The main outcome was the standardized mean difference in the score of the International Index of Erectile Function (IIEF)-5 or IIEF-6. Fifteen RCTs provided information on 1000 men with ED. In the overall NMA, compared to placebo, the combination propionyl L-carnitine (PLC) + acetyl L-carnitine (ALC) + Sildenafil was associated with the highest SUCRA (97%) in improving erectile function score, followed by L-Arginine + Tadalafil (84%), Sildenafil (79%), Tadalafil (72%), and L-Arginine (52%). No other treatment regimen showed efficacy with statistical significance. In patients with organic ED, the efficacy of Sildenafil and Tadalafil was significantly improved by PLC + ALC and L-Arginine, respectively. On the contrary, in non-organic ED, nutraceuticals did not improve the therapeutic performance of daily Tadalafil. This NMA contributes valuable insights into the potential of nutraceutical interventions for ED. We employed strict inclusion criteria related to study design and diagnostic tool, ensuring the assumption of transitivity and the consistency of the analysis. Against a background of general ineffectiveness of most nutraceutical interventions, L-Arginine and the mix PLC + ALC appeared to be of some usefulness in improving erectile function, especially in combination with PDE5i in organic ED.

Isoflavones obtained from red clover improve both dyslipidemia and menopausal symptoms in menopausal women: a prospective randomized placebo-controlled trial

Objective This study aimed to investigate the effects of red clover isoflavones on menopausal symptoms and the lipid profile in menopausal females. Methods This study included postmenopausal women with dyslipidemia. The red clover group (n = 39) received 40 mg isoflavone red clover capsule twice daily for 6 months, while placebo (n = 36) was 40 mg starch capsule twice daily. Data were collected at baseline, 3 months and 6 months. The Menopause Rating Scale (MRS) was applied to calculate subdimension and total scores. Results The two groups were similar in terms of age, MRS and lipid profile at baseline. In the red clover group, MRS scores decreased significantly at both 3 and 6 months. Similarly, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglyceride levels decreased at both 3 months and 6 months. High-density lipoprotein cholesterol increased significantly from baseline to 3 months and 6 months. Except for LDL-C and MRS urogenital score at 3 months, the improvements were significantly in favor of red clover isoflavone treatment. Conclusions Red clover treatment for 3–6 months demonstrated significant improvements in lipid profiles and menopausal symptoms. While promising, further research is crucial to ascertain long-term safety and recommend the use of red clover isoflavones during menopause.

Efficacy and Safety of Modafinil for Treatment of Amphetamine-Type Stimulant Use Disorder: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials: Efficacité et innocuité du modafinil pour le traitement des troubles liés à l'usage de stimulants de type amphétamine : revue systématique et méta-analyse d'essais randomisés contrôlés par placebo.

Amphetamine-type stimulants (ATSs) are related to significant harm worldwide, with limited effective pharmacological treatments for ATS use disorder (ATSUD). Modafinil has been explored as a potential treatment for ATSUD. This systematic review and meta-analysis (PROSPERO ID: CRD42023388487) aimed to evaluate the efficacy and safety of modafinil for the treatment of ATSUD. A comprehensive search of major indexing sources and trial registries, from inception to search date, was conducted on February 15, 2023, and updated on October 31, 2023. Eligible studies were randomized placebo-controlled trials (RCTs) of modafinil in individuals meeting the criteria for the Diagnostic and Statistical Manual of Mental Disorders, fourth and fifth editions, diagnoses of ATSUD. Eligible studies were assessed for risk of bias, using the Cochrane Risk of Bias tool. The primary outcome included the effect of modafinil on ATS use. Secondary outcomes included retention in treatment, ATS craving, treatment discontinuation due to adverse events (AEs), and serious AEs. Subgroup analysis by modafinil dose was conducted where appropriate. Risk ratio (RR) or Peto's odds ratio (OR) was calculated for the meta-analysis of dichotomous variables and standardized mean difference (SMD) was calculated for the random-effect meta-analysis of continuous variables. Five RCTs (N = 451 participants) were included. Modafinil did not significantly impact ATS use (RR = 0.99; 95% CI, 0.97 to 1.02; p = 0.655), retention in treatment (RR = 1.02; 95% CI, 0.91 to 1.14; p = 0.799), ATS craving (SMD = -0.36; 95% CI, -1.19 to 0.47; p = 0.398), or treatment discontinuation due to AEs (Peto's OR = 0.48; 95% CI, 0.20 to 1.14; p = 0.100). These results were consistent across subgroup analyses. More episodes of serious AEs were reported in the modafinil group than in the placebo group, at higher doses (Peto's OR = 4.80; 95% CI, 1.18 to 19.56, p = 0.029). There is currently no evidence suggesting that modafinil has a statistically significant effect on efficacy outcomes in populations with ATSUD. Continued research into effective treatments and harm reduction strategies for ATSUD is essential.

Thyroid hormone receptor-beta agonists in the treatment of metabolically associated steatotic liver disease. Review

Metabolic dysfunction-associated steatotic liver disease, or metabolically-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has become the leading chronic liver disease worldwide in the last decade. The spectrum of MASLD ranges from simple hepatic steatosis to metabolic-associated steatohepatitis (MASH), advanced liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Hepatic inflammation and progressive fibrosis are considered to be the most important driving forces for the progression of MASLD/MASH. Therefore, patients with MASH are a key target group for the development of new therapeutic agents. Although many clinical trials have been conducted in patients with MASLD/MASH over the past two decades, until recently there was no licensed drug for the treatment of this very common metabolic liver disease. Preclinical experimental studies and results from human studies have confirmed the importance of thyroid hormone receptor-β (TGR-β) in the development of hepatic steatosis and stimulated interest in the development of TGR-β agonists as potential treatments for MASLD. The effects of TGR-β agonists, mainly resmetirom, on hepatic and cardiometabolic risk factors have been tested in randomized placebo-controlled trials (RCTs) in patients with MASLD/MASH. As a result of the positive data obtained in the phase III RCT (MAESTRO-NASH), the USA FDA agency on March 14, 2024 accelerated approval of the first TGR-β agonist resmetirom as a drug for the treatment of steatohepatitis associated with metabolic dysfunction. Thus, resmetirom has become the first officially approved drug to be recommended in combination with diet and exercise for use in adults with non-cirrhotic MASH with moderate or advanced liver fibrosis (stages F2-F3 fibrosis).

COVID-19 Modified mRNA “Vaccines”: Lessons Learned from Clinical Trials, Mass Vaccination, and the Bio-Pharmaceutical Complex, Part 1

Our understanding of COVID-19 synthetic, modified mRNA (modmRNA) products and their public health impact has evolved substantially since December 2020. Published reports from the original randomized placebo-controlled trials concluded that the modmRNA injections could greatly reduce COVID-19 symptoms. However, the premature termination of both trials obviated any reliable assessment of potential adverse events due to an insufficient timeframe for proper safety evaluation. Following authorization of the modmRNA products for global distribution, problems with the methods and execution of the trials have emerged. The usual safety testing protocols and toxicology requirements were bypassed. Many key trial findings were either misreported or omitted entirely from published trial reports. By implication, the secondary estimates of excess morbidity and mortality in both trials must be deemed underestimates. Rigorous re-analyses of trial data and post-marketing surveillance studies indicate a substantial degree of modmRNA-related harms than was initially reported. Confidential Pfizer documents had revealed 1.6 million adverse events by August 2022. A third were serious injuries to cardiovascular, neurological, thrombotic, immunological, and reproductive systems, along with an alarming increase in cancers. Moreover, well-designed studies have shown that repeated modmRNA injections cause immune dysfunction, thereby potentially contributing to heightened susceptibility to SARS-CoV-2 infections and increased risks of COVID-19. This paper also discusses the insidious influence of the Bio-Pharmaceutical Complex, a closely coordinated collaboration between public health organizations, pharmaceutical companies, and regulatory agencies. We recommend a global moratorium on the modmRNA products until proper safety and toxicological studies are conducted.

A systematic review and meta-analysis of nutritional and dietary interventions in randomized controlled trials for skin symptoms in children with atopic dermatitis and without food allergy: An EAACI task force report.

This systematic review and meta-analysis aimed to consolidate evidence on dietary interventions for atopic eczema/dermatitis (AD) skin symptoms in children without food allergies, following PRISMA 2020 guidelines. Systematic review updates were conducted in May 2022 and June 2023, focusing on randomized placebo-controlled trials (RCTs) involving children with AD but without food allergies. Specific diets or supplements, such as vitamins, minerals, probiotics, prebiotics, symbiotics, or postbiotics, were explored in these trials. Exclusions comprised descriptive studies, systematic reviews, meta-analyses, letters, case reports, studies involving elimination diets, and those reporting on food allergens in children and adolescents. Additionally, studies assessing exacerbation of AD due to food allergy/sensitization and those evaluating elimination diets' effects on AD were excluded. Nutritional supplementation studies were eligible regardless of sensitization profile. Evaluation of their impact on AD clinical expression was performed using SCORAD scores, and a meta-analysis of SCORAD outcomes was conducted using random-effect models (CRD42022328702). The review encompassed 27 RCTs examining prebiotics, Vitamin D, evening primrose oil, and substituting cow's milk formula with partially hydrolyzed whey milk formula. A meta-analysis of 20 RCTs assessing probiotics, alone or combined with prebiotics, revealed a significant reduction in SCORAD scores, suggesting a consistent trend in alleviating AD symptoms in children without food allergies. Nonetheless, evidence for other dietary interventions remains limited, underscoring the necessity for well-designed intervention studies targeting multiple factors to understand etiological interactions and propose reliable manipulation strategies.

Oxytocin, but not vasopressin, decreases willingness to harm others by promoting moral emotions of guilt and shame

Prosocial and moral behaviors have overlapping neural systems and can both be affected in a number of psychiatric disorders, although whether they involve similar neurochemical systems is unclear. In the current registered randomized placebo-controlled trial on 180 adult male and female subjects, we investigated the effects of intranasal administration of oxytocin and vasopressin, which play key roles in influencing social behavior, on moral emotion ratings for situations involving harming others and on judgments of moral dilemmas where others are harmed for a greater good. Oxytocin, but not vasopressin, enhanced feelings of guilt and shame for intentional but not accidental harm and reduced endorsement of intentionally harming others to achieve a greater good. Neither peptide influenced arousal ratings for the scenarios. Effects of oxytocin on guilt and shame were strongest in individuals scoring lower on the personal distress subscale of trait empathy. Overall, findings demonstrate for the first time that oxytocin, but not vasopressin, promotes enhanced feelings of guilt and shame and unwillingness to harm others irrespective of the consequences. This may reflect associations between oxytocin and empathy and vasopressin with aggression and suggests that oxytocin may have greater therapeutic potential for disorders with atypical social and moral behavior.

In the new era of psychedelic assisted therapy: A systematic review of study methodology in randomized controlled trials.

Recent years have seen a resurgence in randomized, placebo controlled trials (RCTs) utilizing non-classical psychedelics (e.g. 3,4-methyl enedioxy methamphetamine [MDMA]), and classical psychedelics (e.g. psilocybin, lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT/ayahuasca]) in conjunction with assisted therapy (AT) for psychiatric disorders. A notable methodological challenge in psychedelic AT, however, is the complexity of blinding procedures. The lack of efficacious blinding can introduce considerable response bias, reduce internal validity, and compromise participant retention. This systematic review examines design and blinding techniques in RCTs utilizing psychedelics and placebo for the treatment of psychiatric disorders. The aim of this work is to identify factors that may inform future RTC design for conducting psychedelics research. We conducted a systematic review of PubMed, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), Psycinfo, Embase, and Web of Science Core Collection to examine: (1) placebo selection, (2) study design, and (3) integrity of blinding measures. Sixteen publications were identified as meeting the criteria for a systematic review.Our findings suggest that traditional placebo administration is insufficient to control for expectancy confounds. Consequently, experimental methodology that limits personnel unblinding and the use of an active placebo are important considerations when designing prospective clinical studies involving psychedelics.

Preliminary Results from a Phase IV Surveillance Study of Medical Cannabis Use in Australian Patients With Advanced Cancer Receiving Palliative Care.

Introduction: Our research group is conducting three large randomized placebo-controlled trials of medicinal cannabis for cancer symptoms. All participants are invited to take part in a posttrial surveillance study. Methods: Participants were given the manufacturers dosing instructions and liberty to titrate to effect. Data were collected on symptoms (Edmonton Symptom Assessment Scale [ESAS] score), perceived benefits, adverse effects, satisfaction with the product, and dose/frequency. Results: Twenty-six percent of eligible participants consented to take part in the surveillance study. Most participants changed their self-titrated dose at least once. Pain, sleep, and mood were the most frequently cited symptoms which improved. Fatigue, nausea, and cognitive impairment were the most frequently mentioned adverse effects. Conclusion: Participants felt confident making changes to their medicinal cannabis dose within the limits suggested by the manufacturer of each product. A number of benefits and adverse effects were ascribed to the product. Benefits were similar to those described in previous studies.

Management of isolated distal deep vein thrombosis.

Isolated distal deep vein thrombosis (DVT) represents up to 50% of all lower limb DVT in ultrasound series and is a frequent medical condition, which management is not well established. Data arising from registries and non-randomized studies suggest that most distal DVTs do not extend to the proximal veins and have an uneventful follow-up when left untreated. This data had some impact on international recommendations like the American College of Chest Physicians (ACCP), whose last version stated that ultrasound surveillance might be an option for selected low-risk patients. However, robust data arising from randomized studies are scarce. Indeed, only seven randomized trials assessing the need for anticoagulation for calf DVT have been published. Many of these trials had an open-label design and were affected by methodological limitations. When considering randomized placebo-controlled trials, one included low-risk patients and was hampered by a limited statistical power (CACTUS study). Nevertheless, data from this trial tend to confirm that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE but is associated with a higher risk of bleeding. A second randomized placebo-controlled trial did not assess the necessity of anticoagulant treatment but rather the long-term risk of recurrence and compared 6 weeks versus 12 weeks of treatment with rivaroxaban (RIDTS study). Finally, the last available randomized trial compared a 3-month versus a 12-month edoxaban treatment in patients with cancer and mainly asymptomatic distal DVT, detected by systematic compression ultrasonography. Overall, available data suggest that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE. High risk patients (previous VTE, active cancer, inpatients) might benefit from a course of anticoagulant treatment. However, the optimal anticoagulant intensity and duration are uncertain and further studies are needed.

Comparative Efficacy of Drug Interventions on NAFLD Over 24 Weeks: A Traditional and Network Meta-Analysis of Randomized Controlled Trials.

Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency. Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309. Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25mg/day (OR 2.01, 95% CI 1.35-2.98), lanifibranor 1200mg/day (OR 2.39, 95% CI 1.19-4.82) and silymarin (OR 4.54, 95% CI 1.18-17.43) in traditional meta-analysis. The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.

(028) Intracavernosal Injection of Platelet-Rich Plasma for the Treatment of Erectile Dysfunction: A Meta-Analysis of Randomized Placebo-Controlled Trials

Abstract Introduction Erectile dysfunction (ED) affects 3 to 76.5% of men globally. Appropriate treatments for ED patients are vital to ensure their quality of life. However, the present conservative ED treatments cannot reverse the underlying pathology and often lead to discontinuation due to the lack of efficacy. Regenerative therapies, including platelet-rich plasma (PRP), have been gaining increasing interest for the last few years. Preclinical studies suggest that growth factors in PRP may be beneficial in ED. With the increasing evidence of PRP, a meta-analysis has yet to be conducted to determine its efficacy and safety compared to a placebo. Objective To systematically evaluate PRP's efficacy and safety for treating ED based on randomized placebo-controlled trials (RCTs) results. Methods A comprehensive search on PubMed, Scopus, and EMBASE databases was conducted on June 2023 to find relevant articles following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RCTs in English evaluating PRP's efficacy and safety in treating ED were included. The primary outcomes were the International Index of Erectile Function-Erectile Function (IIEF-EF) score at 1-, 3-, and 6-months post-treatment. The secondary analysis includes the proportion of patients who met the minimal clinically important difference (MCID) of IIEF-EF score, IIEF score for sexual satisfaction and overall satisfaction, peak systolic velocity (PSV) in the cavernousal artery, and the complication rate after treatment. Quality of included studies was assessed using JADAD Score and Cochrane RoB2 tools. Meta-analysis with a random or fixed effects model based on the heterogeneity was performed using Revman 5.4. Results From 183 articles in initial research, three RCTs with low risk of bias were reviewed. We included 103 patients in the PRP group and 106 in the placebo group. The baseline of the evaluated score from both groups was comparable despite variable PRP protocol being used. The pooled analysis showed that PRP is associated with higher IIEF-EF scores at 1, 3, and 6 months follow up compared to placebo with a mean difference (MD) of 2.85 (95% CI, 1.68 – 4.03, p: &amp;lt;0.00001), 2.81 (95% CI, 1.57 – 4.05, p: &amp;lt;0.00001), 3.11 (95% CI, 1.96 – 4.27, p: &amp;lt;0.00001). Similarly, the proportion of patients who met MCID and PSV at follow-up also favoured the PRP group. On contrary, the IIEF score for sexual satisfaction and overall satisfaction domain, as well as VAS score post-injection were comparable between groups. No significant adverse event was reported in any study during follow-up. Conclusions The present meta-analysis suggests that PRP is effective and tolerable as a restorative therapy for managing ED patients compared to a placebo. Nevertheless, additional RCTs with more robust data from larger sample sizes and longer-term follow-ups are required to corroborate the findings. Disclosure No.

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation – Clinical and safety results

IntroductionWe investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methodsPatients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. ResultsTwenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01).Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DiscussionOur results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Perioperative oral pregabalin or clonidine in patients undergoing lumbar spine posterior fusion: A randomized controlled trial

ABSTRACT Background Multiple techniques and pharmacological efforts have been tried to control intraoperative hemodynamic fluctuations, reduce perioperative blood loss and severe postoperative pain. This study aimed to assess the perioperative effects of oral premedication with pregabalin or clonidine for lumbar spine posterior fusion under general anesthesia (GA). Outcome measures: Perioperative blood loss, hemodynamics, anesthetics consumption, postoperative pain, and side effects Methods This is a prospective, triple blinded randomized placebo-controlled trial (RCT). Ninety-six adult ASA I-II patients of either sex undergoing lumbar spine posterior fusion were randomly assigned to obtain a placebo (group E), pregabalin 300 mg (group P), or clonidine 200 μg (group C) orally 90 minutes before induction of GA. Trial registration: www.pactr.org with (PACTR201710002416280). Results Preemptive oral pregabalin 300 mg and clonidine 200 μg optimized intraoperative hemodynamics, reduced perioperative blood loss than the placebo group (by 22.2% and 30.7%, respectively), reduced postoperative pain scores, and anesthetic and postoperative analgesic consumption. In addition, they prolonged the duration to the first postoperative analgesic request. There was no major complication in any group. Conclusion Premedication with pregabalin or clonidine reduced perioperative blood loss and optimized intraoperative and postoperative hemodynamics, with the preference for clonidine over pregabalin as well as both reduced postoperative pain scores, analgesic requirements, PONV, and shivering. Sedative drugs should be used in lower doses to avoid oversedation. Pregabalin-associated dizziness and visual disturbance may necessitate extra precautions and patient education.