Placebo-controlled Randomized Clinical Trial Research Articles

Deferiprone in Alzheimer Disease

Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months. The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis). Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%). These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD. ClinicalTrials.gov Identifier: NCT03234686.

Vitamin K2 in Managing Nocturnal Leg Cramps

Currently, there are no treatments for nocturnal leg cramps (NLCs) that have been proven to be both safe and effective. Seeking safe and effective approaches for managing NLCs is of crucial importance. To determine whether vitamin K2 is better than placebo in managing NLCs. This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted in China between September 2022 and December 2023. This study used a volunteer sample comprising community-dwelling individuals 65 years and older with 2 or more documented episodes of NLCs during 2 weeks of screening. Researchers performed a history and physical screening of candidates recruited from the community through advertisements, and eligible participants were randomized in a 1:1 ratio to receive vitamin K2 or a placebo for 8 weeks. Patients orally took capsules containing either vitamin K2 (menaquinone 7), 180 μg, or a similar-looking placebo every day for 8 weeks. The study products were custom manufactured to have identical packaging and for the capsules to have matching appearance and identical excipients that shared similar taste and weight. The primary outcome was the mean number of NLCs per week between the vitamin K2 and the placebo group. Secondary outcomes included the duration of muscle cramps measured in minutes and the severity of muscle cramps assessed using an analog scale ranging from 1 to 10. Among the 310 participants, 111 participants were excluded. Of the 199 enrolled individuals, 108 (54.3%) were female, and the mean (SD) age was 72.3 (5.5) years. A total of 103 patients (51.8%) were randomly assigned to receive vitamin K2 and 96 (48.2%) were assigned to placebo. The mean (SD) baseline weekly frequency of cramps was comparable in both the vitamin K2 group (2.60 [0.81]) and the placebo group (2.71 [0.80]). During the 8-week intervention, the vitamin K2 group experienced a reduction in the mean (SD) weekly frequency of cramps to 0.96 (1.41). Meanwhile, the placebo group maintained mean (SD) weekly frequency of cramps at 3.63 (2.20). The between-group difference was statistically significant (difference, -2.67; 95% CI, -2.86 to -2.49; P < .001). The vitamin K2 group had a more significant mean (SD) reduction in NLC severity (-2.55 [2.12] points) compared with the placebo group (-1.24 [1.16] points). The vitamin K2 group exhibited a more pronounced mean (SD) decrease in the duration of NLCs (-0.90 [0.88] minutes) than the placebo group (-0.32 [0.78] minutes). No adverse events related to vitamin K2 use were identified. This randomized clinical trial showed that vitamin K2 supplementation significantly reduced the frequency, intensity, and duration of NLCs in an older population with good safety. ClinicalTrials.gov Identifier: NCT05547750.

Effect of prophylactic infusion of norepinephrine on the prevention of hypotension during vertebroplasty: a randomized clinical trial

BackgroundTransient hypotension is a common occurrence during the implantation of bone cement. This placebo-controlled randomized clinical trial study investigated the effect of prophylactic infusion of norepinephrine on the incidence of hypotension in senior patients who underwent vertebroplasty.MethodsThe trial recruited patients who were greater than or equal to 65 years of age, had an American Society of Anesthesiologist physical status classification of I to III, and underwent vertebroplasty from August 2020 to August 2021 at the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine in China. The patients were randomly grouped according to whether they received either a norepinephrine infusion of 0.05 µg/kg/min or an equivalent volume of saline 10 min before implantation of bone cement. Intraoperative hemodynamics were monitored continuously by the MostCare system at the following 7 time points: 10 min before implantation of bone cement and immediately, 30 s, 1, 3, 5, and 10 min after implantation of bone cement. We also recorded the number of hypotensive episodes and the total number of vasopressors after implantation of bone cement. Multivariable logistic regression was used to assess the risk factors associated with hypotension after implantation of bone cement.ResultsA total of 63 patients were randomized to the control group (n = 31; median [IQR] age, 74 [69–79] years) and the norepinephrine group (n = 32; median [IQR] age, 75 [71–79] years). The incidence of hypotension in the norepinephrine group was significantly lower than that in the control group after implantation of bone cement (12.5% vs. 45.2%; relative risk [RR], 3.61 [95% CI, 1.13–15.07]; P = 0.005). Moreover, the median (IQR) number of hypotensive episodes (0 [0–0] vs. 0 [0–2]; P = 0.005) and the total number of vasopressors (0 [0–0] vs. 0 [0–1]; P = 0.004) in the norepinephrine group were significantly lower than those in the control group. Furthermore, compared with the baseline, the MAP significantly decreased at 1 min (P = 0.007) and 3 min (P < 0.001) after bone cement implantation in the control group. However, the MAP at 3 min in the norepinephrine group was significantly higher than that in the control group (P < 0.001). The incidence of complications was not different between the groups. In multivariable logistic regression, the FRAIL score (OR, 2.29; 95% CI, 1.21–4.31) was identified as a risk factor associated with hypotension.ConclusionProphylactic infusion of norepinephrine before bone cement implantation can stabilize hemodynamics and reduce the incidence of hypotension after implantation of bone cement.

Expression of PGC-1α, PPAR-α and UCP1 genes, metabolic and anthropometric factors in response to sodium butyrate supplementation in patients with obesity: a triple-blind, randomized placebo-controlled clinical trial.

There is increasing evidence that gut metabolites have a role in the etiology of obesity. This study aimed to investigate the effects of sodium butyrate (NaB) supplementation on the expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1α (PGC-1α), PPAR-α, and uncoupling protein-1 (UCP-1) genes, as well as on the metabolic parameters and anthropometric indices in persons with obesity. In this triple-blind placebo-controlled randomized clinical trial, 50 individuals with obesity were randomly assigned to NaB (600 mg/day) + hypo-caloric diet or placebo group + hypo-caloric diet for 8 weeks. The study measured the participants' anthropometric characteristics, food consumption, and feelings of hunger in addition to the serum levels of metabolic indices and the mRNA expression of the PGC-1α, PPAR-α, and UCP-1 genes in peripheral blood mononuclear cells (PBMCs). PGC-1α and UCP-1 genes expression significantly increased in NaB group compared to the placebo at the endpoint. A significant decrease in weight, BMI, and waist circumference (WC) was observed in NaB group. Among the metabolic factors, NaB significantly decreased fasting blood sugar (FBS) (P = 0.04), low-density lipoprotein cholesterol (LDL-C) (P = 0.038) and increased high-density lipoprotein cholesterol (HDL-C) (P = 0.016). NaB could not significantly change serum GLP-1 level. This study unveiled NaB supplementation alone cannot have significant beneficial effects on anthropometric, and biochemical factors. NaB could affect anthropometric and metabolic risk variables associated with obesity only when prescribed, along with calorie restriction. This study was registered in the Iranian Registry of Clinical Trials ( https://en.irct.ir/trial/53968 ) on 31 January 2021 (registry number IRCT20190303042905N2).

Changing Landscape of Randomized Clinical Trials in Stroke: Explaining Contemporary Trial Designs and Methods.

Evidence generated from randomized clinical trials (RCTs) plays an indispensable role in advancing clinical stroke care. Although the number of stroke-related RCTs published every year has grown exponentially over the past 25 years, the execution and completion of RCTs, particularly those conducted in a hyperacute setting, have grown more complicated and challenging over the years. In addition to the practical challenges associated with conducting a clinical trial, like obtaining human subjects approval, identifying clinical sites, training trial personnel, and enrolling the target number of patients within the available funding and timeline, the complexity of contemporary RCT designs and analyses has become much more exacting. It is no longer sufficient to have a decent understanding of the 2-arm, placebo-controlled RCT, combined with a rudimentary grasp of the P value; things are now much more complicated. Innovations in trial design and analysis, including adaptive, Bayesian, platform, and noninferiority designs, have occurred to address the problems of poor trial efficiency. However, these advances require the end user to have a much greater level of understanding regarding the rationale, conduct, analysis, and interpretation of each design. While these newer designs seek greater efficiency, there are inevitably tradeoffs that need to be understood. In this month's edition of Stroke, we introduce a new series designed to help fill in these knowledge gaps. Over the next few months, 4 papers will be published that address major design innovations (adaptive, Bayesian, platform, and noninferiority) with the aim of illustrating how these approaches can make trials more efficient (where efficiency is defined as getting to the right answer, sooner, with a potentially lower sample size). In addition to introducing this series, this current article also reviews traditional hypothesis testing and the common misinterpretations of the P value; fortunately, new philosophical schools of inference are beginning to vanquish the overreliance on the P value. We are excited about the opportunity to educate the Stroke readership about these new trial designs and the profound implications that they bring.

The effect of prebiotic supplementation on serum levels of tryptophan and kynurenine in obese women with major depressive disorder: a double-blinded placebo-controlled randomized clinical trial

ObjectiveThe objective of the present study was to examine the effect of calorie restricted diet (CRD) plus inulin supplementation on serum levels of tryptophan (Trp), kynurenine (Kyn) and Trp/Kyn ratio in obese women with major depressive disorder (MDD).ResultsIn this double-blind placebo-controlled randomized clinical trial, 51 obese women (BMI = 30–40 kg/m2) with mild MDD were assessed for depression level using Hamilton depression rating scale (HDRS). The patients were randomly allocated into either “Prebiotic group” (received 10 g/day inulin) or “Placebo group” (received 10 g/day maltodextrin). All participants also received individualized CRD. Fasting serum levels of Trp, Kyn, and Trp/Kyn ratio were assessed at baseline and after 8 weeks. Results showed slightly greater increases in serum levels of Trp and Trp/Kyn ratio as well as reductions in serum level of Kyn and HDRS score in prebiotic group than placebo group. However, between group differences in these parameters as well as HDRS score were not statistically significant after adjusting for baseline variables at the end of the trial. Results indicates that CRD accompanied by inulin supplementation (10 g/day) did not influence serum levels of Trp, Kyn and Trp/Kyn ratio as well as HDRS score after 8 weeks.Trial registration: The trial was registered in the Iranian registry of clinical trials at 2018-08-02 (https://www.irct.ir/; registration number: IRCT20100209003320N15).

Advice to People with Parkinson's in My Clinic: Probiotics and Prebiotics.

There is increasing evidence that microbial-based therapies can be useful in people with Parkinson's disease (PD). In this viewpoint, we provide a state-of-the-art review of the clinical and pre-clinical evidence for probiotics and prebiotics in PD. Currently, short-term clinical studies, including double-blind placebo-controlled randomized clinical trials, have demonstrated safety, and efficacy primarily in improving constipation-related symptoms. Pre-clinical studies consistently reported improvements in a range of biological markers and outcomes, including evidence for attenuation of gut dysfunction and neuroprotection. Bacteria from the genus Lactobacillus and Bifidobacterium have been the most frequently studied both in clinical and pre-clinical probiotics studies, while research into prebiotics is still limited and primarily involved resistant starch and fructooligosaccharides. We provide practical suggestions for clinicians on how to advise patients in the clinic regarding these popular treatments, and important caveats to be aware of. Finally, areas for further advancements are highlighted. It is envisaged that in the future, microbial-based therapies may benefit from personalization based on an enhanced understanding of a whole range of host factors and host-microbiome interactions.

Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity

Sperm production depends on proper Sertoli-germ cell interaction, and we hypothesized that receptor activator of nuclear factor κB ligand (RANKL) activity in Sertoli cells may influence spermatogenesis. Treatment with the RANKL inhibitor denosumab, normally used to treat osteoporosis, increased testicular weight, inhibin B, and germ cell proliferation in exvivo testis cultures and invivo in a humanized RANKL mouse. The effect on germ cell proliferation was positively associated with baseline serum concentrations of anti-müllerian hormone (AMH). In accordance, denosumab increased germ cell proliferation in exvivo human testis cultures with low/moderate but not severe impairment of Sertoli cell function. In a placebo-controlled randomized clinical trial, denosumab had no effect on semen quality but increased sperm concentration in a subgroup of infertile men with serum AMH ≥38 pmol/L at baseline. In conclusion, high serum AMH may increase the probability of a beneficial response to denosumab treatment in infertile men, thus suggesting a possible venue for precision medicine in male infertility.

Prior Local Therapy and First-Line Apalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Preclinical studies suggest that exposure to prostate-directed local therapy (LT) may influence the efficacy of subsequent systemic therapy including androgen receptor pathway inhibitors. However, there is insufficient clinical evidence to support this premise in patients with nonmetastatic castrate-resistant prostate cancer (nmCRPC). To determine whether exposure to prior prostate-directed LT (radical prostatectomy [RP], radiation therapy [RT], or both) played any effect-modifying role in the treatment effect of apalutamide on metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC. This post hoc secondary analysis used individual patient data from SPARTAN (Study of Apalutamide [ARN-509] in Men With Non-Metastatic Castration-Resistant Prostate Cancer), a phase 3, double-blinded, placebo-controlled randomized clinical trial conducted at 332 sites in 26 countries. Between October 14, 2013, and December 15, 2016, patients with nmCRPC and a prostate-specific antigen doubling time of 10 months or less were randomly assigned to apalutamide vs placebo; all patients received androgen deprivation therapy. The final data analysis was performed on December 31, 2023. Prior prostate-directed LT. Separate Cox proportional hazards regression models were constructed for OS and MFS, which included prior LT, treatment group, and an interaction term, in addition to a minimally sufficient set of confounders. Adjusted hazard ratios (HRs) with 95% CIs for MFS and OS were determined for the apalutamide groups with or without prior LT. Among the 1179 evaluable patients included in this analysis, 795 received prior LT and 384 did not. The median age of patients with and without prior LT was 70 (IQR, 45-90) years and 75 (IQR, 50-95) years, respectively. The median follow-up was 52.0 (IQR, 51.5-52.8) months. A differential treatment effect of apalutamide on MFS was observed between patients with and without prior LT (P for interaction = .009), with greater benefits for those with prior LT (adjusted HR, 0.22 [95% CI, 0.17-0.27]) compared with those without prior LT (adjusted HR, 0.35 [95% CI, 0.25-0.51]). However, there was insufficient evidence of a differential treatment effect on OS among subgroups stratified by exposure to prior LT (P for interaction = .23), with improved OS in the subgroup with prior LT (adjusted HR, 0.72 [95% CI, 0.57-0.92]) but no significant difference in OS in the subgroup without prior LT (adjusted HR, 0.92 [95% CI, 0.64-1.31]). This post hoc analysis of the SPARTAN trial provides evidence of an interaction between prior LT and apalutamide in patients with nmCRPC, with a clinically significant and more favorable treatment effect from apalutamide on MFS among patients with prior LT. Further studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT01946204.

Dexmedetomidine use during orthotopic liver transplantation surgery on early allograft dysfunction: a randomized controlled trial.

Previous studies have shown a protective effect of dexmedetomidine use in kidney transplantation. In contrast, it is not known whether intraoperative administration of dexmedetomidine can reduce early allograft dysfunction (EAD) incidence following liver transplantation. To investigate the effect of dexmedetomidine use during surgery on EAD following orthotopic liver transplantation (OLT). This is a single-center, double-blinded, placebo-controlled randomized clinical trial. Three hundred thirty adult patients undergoing OLT were enrolled from 14th January 2019 to 22nd May 2022. Patients received dexmedetomidine or normal saline during surgery. One year follow-ups were recorded. Patients were randomized to two groups receiving either dexmedetomidine or normal saline intraoperatively. For patients in the dexmedetomidine group, a loading dose (1μg/kg over 10min) of dexmedetomidine was given after induction of anesthesia followed by a continuous infusion (0.5μg/kg /h) until the end of surgery. For patients in the normal saline group, an equal volume loading dose of 0.9% saline was given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. The primary outcome was EAD. Secondary outcomes included primary graft nonfunction, acute kidney injury, and acute lung injury/acute respiratory distress syndrome. Of 330 patients included in the intention-to-treat analysis, 165 were in the dexmedetomidine group [mean (SD) age, 49 (10) years; 117 (70.9%) men], and 165 were in the normal saline group [mean SD age, 49 (9) years; 118 (74%) men]. 39 (24.4%) patients in the dexmedetomidine group and 31 (19.4%) in normal saline group developed EAD and the difference was statistically insignificant ( P =0.28). Secondary outcomes including primary graft nonfunction and acute kidney injury was similar between the two groups. Intraoperative administration of dexmedetomidine did not reduce EAD rate after OLT.

O88 REDUCTION IN SYSTOLIC BLOOD PRESSURE FOLLOWING DIETARY FIBRE INTERVENTION IS DEPENDENT ON BASELINE GUT MICROBIOTA COMPOSITION

Background/Objective: Dietary interventions high in fibre have been shown to lower blood pressure (BP). This effect is via the gut microbiota, via fermentation of fibre and production of metabolites called short-chain fatty acids (SCFAs). Not all patients respond to dietary fibre interventions for unclear reasons. We aimed to determine if we can identify fibre-responders based on their gut microbiota and production of SCFAs. Methods: We performed a phase II cross-over placebo-controlled randomised clinical trial in untreated hypertensive patients. Twenty treatment-naive participants with hypertension received 40 g per day of fermentable fibre delivered as acetylated and butyrylated high amylose maize starch (HAMSAB) or the placebo for 3 weeks. Blood pressure was monitored at baseline and endpoint by ambulatory BP monitoring, with those experiencing a reduction of ≥2 mmHg in systolic BP classified as responders. The microbiota was determined by sequencing the V4-V5 region of the 16S rRNA gene in baseline stool samples. The relationship between baseline gut microbiota and response to dietary intervention was assessed with the MaAsLin2 package. Plasma SCFAs levels were quantified by mass spectrometry. Results: We observed a placebo-subtracted mean 24-hour systolic BP of –6.1 mmHg (p=0.03, reported in Jama et al., 2023 Nature Cardiovascular Research), with 14 (70%) individuals classified as responders and 6 (30%) as non-responders. Genera significantly enriched in responders included Dialister (β=1.29, q=1.921x10-134), Coprococcus (β=1.26, q=3.282x10-121), Bifidobacterium (β=1.67, q=1.11x10-81), Ruminococcus (β=0.161, q=1.11x10-8), and Roseburia (β=0.82, q=4.275x10-2). Responders also produced higher levels of the SCFAs butyrate (mean±SEM, non-responders 4.95±2.4 vs responders 51.15±14.7, p=0.0096), but no difference in other SCFAs. Conclusions: Participants who experienced a decrease in systolic BP following a dietary fibre intervention had increased bacterial genera known to contain species that produce SCFAs (Bifidobacterium, Roseburia, Ruminococcus) at baseline, and were able to produce more butyrate. These data suggest that baseline microbiota composition contributes to the response to dietary fibre intervention trials in people with hypertension, likely via increased capacity to produce butyrate.

Systemic and cerebro-cardiac biomarkers following traumatic brain injury: an interim analysis of randomized controlled clinical trial of early administration of beta blockers

This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = − 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI.Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28–30, 2024, in Estoril, Lisbon, Portugal.

Routine Protamine Administration for Bleeding in Transcatheter Aortic Valve Implantation

Vascular complications after transfemoral transcatheter aortic valve implantation (TAVI) remain an important cause of procedure-related morbidity. Routine reversal of anticoagulation with protamine at the conclusion of transfemoral TAVI could reduce complications, but data remain scarce. To evaluate the efficacy and safety of routine protamine administration after transfemoral TAVI. The ACE-PROTAVI trial was an investigator-initiated, double-blind, placebo-controlled randomized clinical trial performed at 3 Australian hospitals between December 2021 and June 2023 with a 1-year follow-up period. All patients accepted for transfemoral TAVI by a multidisciplinary heart team were eligible for enrollment. Eligible patients were randomized 1:1 between routine protamine administration and placebo. The coprimary outcomes were the rate of hemostasis success and time to hemostasis (TTH), presented as categorical variables and compared with a χ2 test or as continuous variables as mean (SD) or median (IQR), depending on distribution. The major secondary outcome was a composite of all-cause death, major and minor bleeding complications, and major and minor vascular complications after 30 days, reported in odds ratios (ORs) with 95% CIs and P values. The study population consisted of 410 patients: 199 patients in the protamine group and 211 in the placebo group. The median (IQR) patient age in the protamine group was 82 (77-85) years, and 68 of 199 patients receiving protamine (34.2%) were female. The median (IQR) patient age in the placebo group was 80 (75-85) years, and 89 of 211 patients receiving the placebo (42.2%) were female. Patients receiving up-front protamine administration had a higher rate of hemostasis success (188 of 192 patients [97.9%]) than patients in the placebo group (186 of 203 patients [91.6%]; absolute risk difference, 6.3%; 95% CI, 2.0%-10.6%; P = .006); in addition, patients receiving up-front protamine had a shorter median (IQR) TTH (181 [120-420] seconds vs 279 [122-600] seconds; P = .002). Routine protamine administration resulted in a reduced risk of the composite outcome in the protamine group (10 of 192 [5.2%]) vs the placebo group (26 of 203 [12.8%]; OR, 0.37; 95% CI, 0.1-0.8; P = .01). This difference was predominantly driven by the difference in the prevalence of minor vascular complications. There were no adverse events associated with protamine use. In the ACE-PROTAVI randomized clinical trial, routine administration of protamine increased the rate of hemostasis success and decreased TTH. The beneficial effect of protamine was reflected in a reduction in minor vascular complications, procedural time, and postprocedural hospital stay duration in patients receiving routine protamine compared with patients receiving placebo. anzctr.org.au Identifier: ACTRN12621001261808.

Effectiveness of Low-Level Laser Therapy in Orchialgia After Varicocelectomy Surgery.

Introduction: The management of chronic groin and scrotal content pain (orchialgia) is a complex condition after varicocelectomy that is encountered by most practicing clinicians. The aim of this study was to evaluate the effectiveness of low-level laser therapy (LLLT) in orchialgia after varicocelectomy surgery. Methods: This study was performed as a double-blind, placebo-controlled randomized clinical trial in which sixty patients with orchialgia after varicocelectomy were randomly divided into three groups of 20 as follows: (1) low-level laser group with red (650 nm, 50 mW), (2) low-level laser group with infrared (IR) (820 nm, 100 mW), and (3) laser placebo group. The treatment protocol consisted of 15 minutes, three times a week, for only 12 sessions. Then, the patients were evaluated for pain and sexual satisfaction during the 12-week follow-up. Results: The pain score in the two groups of low-level laser with red light and IR spectra showed a significant relief (P<0.05) 6 and 12 weeks after starting the treatment, In addition, a significant increase was observed in the level of sexual satisfaction in the red and infrared spectra LLLT groups (P<0.05). Conclusion: We concluded that the use of LLLT with red light (650 nm, 50 mW)/IR (820 nm, 100 mW) spectra with power of 6-25 J/cm2/day in 15 minutes, three times a week, for 12 sessions can significantly reduce pain and increase sexual satisfaction in these patients.

Efficacy of Omega-3 in Improving Sleep Quality of Healthcare Workers with Shiftwork Sleep Disorder: Phase III, Double-blind, Placebo-controlled Trial Study Protocol (SLEEP-O3 Trial)

Introduction: Healthcare workers are especially vulnerable to sleep disturbances, including shift work sleep disorder (SWSD). Even though omega-3 supplementation has been studied to enhance sleep quality in different populations, there is lack of evidence to support its effectiveness in SWSD. This trial aims to evaluate this compound potential benefits towards health care personnel suffering from SWSD. Methods: This study protocol consists of a phase III, single-center, double-blind, placebo-controlled randomized clinical trial. Participants will receive sleep hygiene orientation in addition to either omega-3 dietary supplementation or placebo for 8 weeks. The primary outcome will be sleep quality as measured by the Pittsburgh Sleep Quality Index and one of the secondary outcomes would be actigraphy as a reliable sleep assessment. The sample size will be 136 subjects. Discussion: The importance of improving sleep quality of health care workers relies on its impact on their wellness, and on patient safety. Sleep deprivation and disorders are responsible for multiple workplace errors and worse health outcomes alike. This trial can help determine if omega-3 supplementation can contribute to ameliorate sleep disturbances in health care professionals.

The effect of myo-inositol supplementation on AMPK/PI3K/AKT pathway and insulin resistance in patients with NAFLD.

Insulin resistance (IR) is the pivotal pathological hit in non-alcoholic fatty liver disease (NAFLD). There is specific attention to combination/conjugated therapies for NAFLD management. As myo-inositol (MI) has been shown to improve IR in animal and human trials, this study aimed to investigate the influence of MI supplementation on glycemic response and IR through AMPK/PI3K/AKT signaling pathway in obese patients with NAFLD. This double-blinded placebo-controlled randomized clinical trial was conducted on 48 obese (BMI = 30-40 kg/m2) patients with NAFLD who were randomly assigned to receiving either MI (4 g/day) or placebo (maltodextrin 4 g/day) group for 8 weeks. Before and after the trial, weight, height, serum glycemic parameters (inc. fasting glucose and insulin) as well as IR indices were assessed. Moreover, the mRNA expression levels of AMPK, AKT, and PDK-1 in peripheral blood mononuclear cells (PBMCs) were determined. MI supplementation resulted in significant increases in the fold changes of AMPK, AKT, and PDK-1 genes (p = .019, p = .049, and p = .029, respectively). Indeed, IR improved in terms of all IR indices in MI group (p < .05) after adjusting for the confounders, apart from quantitative insulin sensitivity check index (QUICKI). The results showed that MI supplementation not only upregulated AMPK, AKT, and PDK-1 mRNA in PBMCs but also improved IR in obese patients with NAFLD.

2023 Brazilian Society of Rheumatology guidelines for the treatment of systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc.MethodsA systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed.ResultsSix recommendations were elaborated regarding the pharmacological treatment of Raynaud’s phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found.ConclusionThese guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice.

A phase 2b double-blind placebo-controlled randomized clinical trial of SB-061, an aggrecan mimetic, in patients with symptomatic knee osteoarthritis

ObjectivesTo evaluate the efficacy and safety of intra-articular injections of a novel aggrecan mimetic, SB-061, in subjects with knee OA. MethodsThis was a randomized, placebo-controlled, double-blind phase II study comparing intra-articular injections of SB-061 with placebo (isotonic saline) for 52 weeks, administered at baseline, Wk 16, and Wk 32. Eligible subjects had a KL grade of 2 or 3 on X-ray of the target knee and a WOMAC pain score ≥20 out of 50 at screening and baseline visits. Subjects having any other knee condition were excluded. Use of analgesics was prohibited, except for rescue medication. The primary endpoint was change from baseline (CFB) in WOMAC pain at Week 8. Secondary endpoints were CFB in WOMAC function and total, ICOAP, PGA, and 20-meter walk test. Exploratory endpoints included structural CFB in MRI entities. Results288 subjects were randomized to SB-061 (n=145) or placebo (n=143), and 252 (87.5%) completed injections. The groups were comparable at baseline. The primary endpoint was not met, as no significant difference in the CFB of the WOMAC pain score at Week 8 between groups was observed, nor at any other time point during the study. Similarly, neither of the secondary or exploratory endpoints indicated any significant difference between groups. The frequency and type of adverse events was similar between groups. SB-061 was well-tolerated. ConclusionIntra-articular injections of SB-061 administered at baseline, Wk 16, and Wk 32, over one year in subjects with knee OA was safe but did not show any statistically significant effect on knee pain nor on other symptomatic or structural entities compared to placebo. Trial registration number EudraCT No2019-004515-31

Varenicline and Nicotine Replacement Therapy for Smokers Admitted to Hospitals

Varenicline is the most effective sole pharmacotherapy for smoking cessation. If used in combination with nicotine replacement therapy (NRT), cessation rates may be further improved, but the efficacy and safety of the combination need to be evaluated. To examine whether hospitalized smokers treated with varenicline and NRT lozenges achieve higher prolonged smoking abstinence rates compared with those treated with varenicline alone. A double-blind, placebo-controlled randomized clinical trial was conducted in adult medical or surgical inpatients of 5 Australian public hospitals with a history of smoking 10 cigarettes or more per day, interested in quitting, and available for 12-month follow-up between May 1, 2019, and May 1, 2021 (final 12-month data collection in May 2022). Data analysis was performed from June 1 to August 30, 2023. A 12-week varenicline regimen was initiated during hospitalization at standard doses in all participants. Participants were randomized to additionally use NRT (2 mg) or placebo lozenges if there was an urge to smoke. Behavioral support (Quitline) was offered to all participants. The primary outcome was biochemically verified sustained abstinence at 6 months. Secondary outcomes included self-reported prolonged abstinence, 7-day point prevalence abstinence (3, 6, and 12 months), and medicine-related adverse events. A total of 320 participants (mean [SD] age, 52.5 [12.1] years; 183 [57.2%] male) were randomized. The conduct of biochemical verification was affected by COVID-19 restrictions; consequently, the biochemically verified abstinence in the intervention vs control arms (18 [11.4%] vs 16 [10.1%]; odds ratio [OR], 1.14; 95% CI, 0.56-2.33) did not support the combination therapy. The secondary outcomes in the intervention vs control arms of 7-day point prevalence abstinence at 6 months (54 [34.2%] vs 37 [23.4%]; OR, 1.71; 95% CI, 1.04-2.80), prolonged abstinence at 12 months (47 [29.9%] vs 30 [19.1%]; OR, 1.77; 95% CI, 1.05-3.00), and 7-day point prevalence abstinence at 12-months (48 [30.6%] vs 31 [19.7%]; OR, 1.79; 95% CI, 1.07-2.99) significantly improved with the combination therapy. The self-reported 6-month prolonged abstinence (61 [38.6%] vs 47 [29.7%]; OR, 1.49; 95% CI, 0.93-2.39) favored the combination therapy but was not statistically significant. Medicine-related adverse events were similar in the 2 groups (102 [74.5%] in the intervention group vs 86 [68.3%] in the control group). In this randomized clinical trial of the combination of varenicline and NRT lozenges in hospitalized adult daily smokers, the combination treatment improved self-reported abstinence compared with varenicline alone, without compromising safety, but it did not improve biochemically validated abstinence. anzctr.org.au Identifier: ACTRN12618001792213.

Diazoxide for Severe or Recurrent Neonatal Hypoglycemia

Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia. This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours). Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol. The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks. Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo. In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo. ANZCTR.org.au Identifier: ACTRN12620000129987.