Placebo Group Research Articles

Repeat-dose dexamethasone to prevent pain relapse after total knee arthroplasty in high-pain-response patients: A randomised, double-blind, placebo-controlled superiority trial.

Peri-operative glucocorticoids reduce pain after total knee arthroplasty, with evidence suggesting potential benefits of increased dosing in specific patient groups. However, the impact of repeat-dose glucocorticoids has not been studied in high-pain-response patients receiving pre-operative high-dose glucocorticoids. To investigate the effect on pain of an oral dose of dexamethasone after total knee arthroplasty in selected high-pain-response patients who had received a pre-operative high dose of intravenous dexamethasone (1 mg kg-1). Randomised, double-blind, placebo-controlled superiority study. A multicentre study conducted at two major arthroplasty centres in Denmark from November 2021 to March 2024. One hundred and ten patients undergoing total knee arthroplasty who had received multimodal analgesia including pre-operative intravenous dexamethasone 1 mg kg-1. Selection criteria included a Pain Catastrophising Scale score greater than 20 and moderate-to-severe pain (VAS >30) during walking 24 h postoperatively. Patients were randomised to either oral dexamethasone 24 mg or placebo on postoperative day 1. The primary outcome was the proportion of patients experiencing moderate-to-severe pain during walking at 48 h postoperatively. Secondary outcomes included pain scores at various time points within 1 week postoperatively, rescue analgesics, quality of sleep, length of hospital stay and morbidity with follow-up at 30 days. At 48 h postoperatively, 65% of patients in the dexamethasone group and 79% in the placebo group reported moderate-to-severe pain during walking: odds ratio 0.48 [95% confidence interval (CI), 0.20 to 1.16]; P = 0.100. The mean ± SD Visual Analogue Scale (VAS) at 48 h during walking was 43 ± 21 in the dexamethasone group and 51 ± 22 in the placebo group (P = 0.051). There were no differences between the groups regarding secondary pain outcomes or the use of rescue analgesics. The administration of a high oral dose of dexamethasone following an initial pre-operative dose of 1 mg kg-1 intravenously in selected high-pain-response patients had no effect on postoperative pain following total knee arthroplasty. ClinicalTrials.gov identifier NCT05563155 (clinicaltrials.gov/study/NCT05563155?id=NCT05563155&rank=1).

Randomized, Placebo-Controlled, Triple-Blind Clinical Trial of Ivabradine for the Prevention of Cardiac Dysfunction During Anthracycline-Based Cancer Therapy.

Cancer therapy-related cardiac dysfunction frequently occurs in patients receiving anthracycline. Ivabradine reduces heart rate without affecting contractility and showed anti-inflammatory, antioxidant, and antiapoptotic effects in experimental cardiotoxicity models. This study aims to evaluate the effect of ivabradine on cancer therapy-related cardiac dysfunction in patients with lymphoma or sarcoma treated with anthracycline. In a randomized, triple-blind trial, patients starting anthracycline therapy received either ivabradine 5 mg twice daily or placebo until 30 days after completing treatment. The primary outcome was the incidence of cardiotoxicity measured as a ≥10% relative reduction in global longitudinal strain at 12 months from baseline. Secondary outcomes included 12-month clinical outcomes, a ≥10% decrease in the left ventricular ejection fraction to <55%, diastolic dysfunction, and troponin T and N-terminal pro-B-type natriuretic peptide levels. This study enrolled 107 patients (51 in the ivabradine group and 56 in the placebo group). The median dose of anthracycline was 300 mg/m2 (250-300 mg/m2) in both groups. Cardiotoxicity measured as a ≥10% relative reduction in global longitudinal strain at 12 months was reached in 57% versus 50% in the ivabradine and placebo groups (odds ratio, 1.32 [95% CI, 0.61-2.83]; P=0.477). Fewer patients in the ivabradine group than in the placebo group had troponin T levels ≥14 ng/L (16 [39.0%] versus 23 [62.2%]; P=0.041) at 6 months, with this difference not maintained at the 12-month follow-up. In addition, there were no differences in the other secondary outcomes. A fixed 10 mg/day dose of ivabradine does not protect patients with cancer against anthracycline cardiotoxicity. URL: https://clinicaltrials.gov/; Unique Identifier: NCT03650205.

Clinical Efficacy and Safety of the Herbal Prescription, HH333, in Preventing Recurrent Stroke in Patients With Ischemic Stroke Induced by Small-Vessel Disease: Protocol for Multicenter, Double-Blind, Randomized, Prospective, Pilot Clinical Trial.

Patients with ischemic stroke are at high risk of recurrence, making preventive care an important factor. Current antiplatelet therapy for recurrence prevention treatment has several limitations. Recent retrospective observational studies suggested that HH333, an herbal prescription, has an inhibitory effect on stroke recurrence in small-vessel diseases. This study aims to propose a protocol for evaluating the efficacy and safety of HH333 in patients with ischemic stroke induced by small-vessel disease. In this multicenter, double-blind, randomized, prospective, pilot clinical trial, 236 patients from 3 university Korean medicine hospitals in South Korea with ischemic stroke caused by small-vessel disease will be recruited and randomly assigned to either the HH333 or the placebo group. Both patients and investigators will be blinded to prevent access to the allocation results. The HH333 group will take 2 capsules of HH333 once daily for 720 days, whereas the placebo group will take HH333 placebo capsules in the same manner. Efficacy will be assessed using the recurrence rate of ischemic stroke, which will be assessed on days 30, 90, 180, 270, 360, 450, 540, 630, 720, and 750 after starting the medication. The effects on quality of life and fatigue with the Fatigue Severity Scale (FSS), Fatigue Assessment Scale (FAS), and Korean Patient Health Questionnaire (K-PHQ-9), functional improvement with Korean National Institutes of Health Stroke Scale (K-NIHSS), modified Rankin Scale (mRS), Korean modified Barthel Index (K-mBI), and Korean Montreal Cognitive Assessment (K-MoCA) and Pattern Identification also will be evaluated on days 0, 90, 180, 270, 360, 450, 540, 630, and 720 after starting the medication. Safety will be evaluated by performing blood and urine tests and electrocardiography on days 30, 90, 180, 270, 360, 450, 540, 630, and 720 after starting the medication. Recruitment for the study started on May 22, 2024, and is scheduled to end on November 30, 2026. As of November 13, 2024, a total of 12 participants have been randomized. The protocol will provide a detailed process for a clinical trial evaluating the efficacy of preventing recurrent ischemic stroke caused by small-vessel disease and improving neurologic symptoms and the safety of HH333 in ischemic stroke. The results of this study provide a basis for alternative treatments to prevent and treat ischemic stroke. Clinical Research Information Service KCT0009431; https://tinyurl.com/y2ctvje8. DERR1-10.2196/70953.

Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory bowel disease leading to symptoms such as abdominal pain, diarrhea, weight loss, fatigue, and complications such as strictures and fistulas. Ustekinumab (CNTO 1275) and briakinumab (ABT-874) are monoclonal antibodies that target the standard p40 subunit of the cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of CD. Briakinumab has been withdrawn for the treatment of CD, making ustekinumab the only available antibody against the p40 subunit of interleukin-12 and interleukin-23 approved for this purpose. To assess the benefits and harms of anti-IL-12/23p40 antibodies for induction of remission in CD, as compared to no treatment, placebo, other drug treatment, or varying dosing schedules. We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and MEDLINE (from inception to 2 February 2024) and Embase (from inception until 12 August 2022). We also searched ClinicalTrials.gov, WHO ICTRP, references, and conference abstracts to identify additional studies. We included randomized controlled trials (RCTs) of at least four weeks' duration in which monoclonal antibodies against IL-12/23p40 were compared to placebo, no treatment, or another active comparator in people with active CD. We also included trials examining different doses of antibodies against IL-12/23p40. Two review authors independently screened studies for inclusion and extracted data. We assessed the methodological quality of the included studies using Cochrane's RoB 2 tool. The primary outcome was failure to induce clinical remission by week 8, or 6 to 12 as available. Secondary outcomes included failure to induce clinical improvement (clinical response), induction of endoscopic remission, quality of life, and adverse events, serious adverse events, and withdrawals due to adverse events. We calculated the risk ratio (RR) or risk difference (RD) and 95% confidence intervals (95% CI) for each outcome unless substantial heterogeneity was detected. We analyzed data on an intention-to-treat basis. We assessed the certainty of the evidence using the GRADE approach. Eight RCTs involving a total of 3224 participants with CD met the inclusion criteria. All studies were double-blinded. We assessed the risk of bias for most outcomes as either low risk of bias or some concerns. Based on a pooled analysis of three trials, ustekinumab decreased the number of participants failing to achieve clinical remission at eight weeks when compared to placebo. Seventy-four per cent (693/938) of participants in the ustekinumab group and 87% (421/483) of those in the placebo group did not enter clinical remission (RR 0.85, 95% CI 0.81 to 0.89; 3 studies; 1421 participants; high-certainty evidence). Treatment with ustekinumab likely did not lead to more serious adverse events when compared to placebo, with 5% (48/966) and 6% (30/505) of participants affected in the ustekinumab and placebo groups, respectively (RD -0.01, 95% CI -0.03 to 0.01; 3 studies; 1471 participants; moderate-certainty evidence). A single small study in children compared two different induction doses of ustekinumab. The evidence for this outcome is very uncertain due to wide CIs. Eighty-one per cent (17/21) of participants receiving the higher induction dose (9 mg/kg or 390 mg) did not enter clinical remission at eight weeks, compared to 78% (18/23) of participants receiving the lower induction dose of 3 mg/kg or 130 mg (RR 1.03, 95% CI 0.77 to 1.39; 1 study; 44 participants; very low-certainty evidence). Separate safety data for the eight-week time point were not available for this comparison. Based on one trial comparing ustekinumab to adalimumab, the evidence is very uncertain about which is the more beneficial drug. Fifty per cent (95/191) of participants receiving ustekinumab did not enter remission compared to 52% (101/195) of participants receiving adalimumab (RR 0.96, 95% CI 0.79 to 1.17; 1 study; 386 participants; very low-certainty evidence). Separate results on adverse events at eight weeks were not reported for this comparison. Ustekinumab reduces the risk of people with CD failing to enter clinical remission at eight weeks. It probably does not lead to more serious adverse events when compared to placebo. There were inadequate data to conclude the more effective induction dose of ustekinumab in children. No studies evaluated adverse events at eight weeks for this comparison. There may be little to no difference between ustekinumab and other biologics, such as adalimumab or guselkumab, in inducing clinical remission at week 8, but the evidence is very uncertain, and separate data on adverse events at eight weeks were not available.

Lameness improvement in horses with distal tarsal pain after intra-articular injection of botulinum neurotoxin type A.

To evaluate the effect of IA injections of botulinum toxin type A (BoNT-A) in horses with chronic, naturally occurring distal tarsal osteoarthritis. 9 horses were selected after physical and radiographic assessments. Horses also underwent an objective lameness examination and were included if they had a hindlimb impact lameness (Pmin ≥ 3 mm), which positively responded (≥ 50%) to the tarsometatarsal and centrodistal joints' anesthetic block. Horses randomly received an intra-articular injection of BoNT-A or an equivalent volume of saline solution. Horses were reevaluated at postinjection days (PIDs) 1, 7, 15, 30, 60, 90, 120, 150, and 180. Success criteria included a decrease in Pmin (≤ 3 mm) or an abolishment of lameness on the baseline lame limb with lameness shifting to the contralateral limb. A percentage of lameness improvement was calculated for all horses at all timepoints. 5 horses were included in the BoNT-A group, whereas 4 individuals were allocated in the placebo group. A significant improvement (P < .05) was observed in horses from the BoNT-A group when compared to placebo at PIDs 90, 120, 150, and 180. Two of 5 horses (40%) from the BoNT-A group had an absolute improvement (100%) in lameness at all the timepoints. Higher percentages of lameness improvement were observed at PID 60. The results of this study suggest that the intra-articular injection with 50 U of BoNT-A was effective in reducing lameness in horses with distal tarsal osteoarthritis, mainly 90 days after injection. Botulinum toxin type A can be considered as an option for managing horses with chronic osteoarthritis.

Modic Change Edema in Chronic Low Back Pain Treated with Infliximab or Placebo: The BackToBasic Trial.

Randomized trial. To assess whether infliximab is superior to placebo in reducing Modic change (MC) edema, and whether MC edema or apparent diffusion coefficient (ADC) values of MCs modify the effect of infliximab on disability or low back pain (LBP). In the present BackToBasic trial, infliximab did not reduce disability or LBP at 5-months follow-up in patients with chronic LBP and MC type 1. The effect on MC edema and in edema-defined subgroups is unknown. Patients with chronic LBP and type 1 MCs were randomized to receive four infliximab infusions or placebo over 98 days. MC edema was assessed using short tau inversion recovery imaging. Primary edema variables were maximum baseline edema volume (Volmax) ≥25% of vertebral body marrow (yes/no) and reduced edema at 6 months (yes/no). Maximum MC-related ADC value (0-100%) was measured at baseline. Outcomes at 5 months were the Oswestry Disability Index (ODI, 0-100, primary outcome) and LBP intensity (0-10). The analyses included logistic regression and linear mixed-effects models. 128 patients (mean age 43 years, 84 women) were included, of which78 were treated per protocol (PP). The odds ratio for reduced MC edema at 6 months in the infliximab vs placebo group was 2.2 (95% confidence interval [CI] 0.8, 5.8; P=0.12) in the primary PP analysis and 2.1 (95% CI 1.02, 4.5; P=0.04) in the total sample. Neither MC edema nor ADC values modified the effect of infliximab on ODI or LBP intensity. At 5 months, the effect in the Volmax ≥25% group was -4.2 ODI points (95% CI -11.4, 3.1; primary PP analysis). Infliximab had no clinically relevant edema reducing effect. MC edema did not modify the effect of infliximab on disability or LBP, nor did the MC-related ADC value. Level 2.

Deucravacitinib in Patients With Inflammatory Bowel Disease: 12-Week Efficacy and Safety Results From Three Randomized Phase 2 Studies in Crohn's Disease and Ulcerative Colitis.

Tyrosine kinase 2 is a downstream intracellular mediator of interleukin-23 signaling, which has a key role in the pathogenesis of inflammatory bowel disease. Deucravacitinib is a novel, oral, selective, allosteric tyrosine kinase 2 inhibitor currently approved for the treatment of adults with moderate to severe plaque psoriasis. Here we describe three randomized, double-blind, placebo-controlled phase 2 studies of deucravacitinib in patients with moderately to severely active Crohn's disease (LATTICE-CD [NCT03599622]) or ulcerative colitis (LATTICE-UC [NCT03934216] and IM011-127 [NCT04613518]). Patients were randomized to receive placebo or twice-daily deucravacitinib 3mg or 6mg (LATTICE-CD), 6mg (LATTICE-UC), or 12mg (IM011-127) for 12 weeks. Coprimary endpoints for LATTICE-CD were clinical remission and endoscopic response at Week 12. The primary endpoint was clinical remission (per modified Mayo score) at Week 12 for LATTICE-UC and clinical response (per modified Mayo score) at Week 12 for IM011-127. A total of 239 (LATTICE-CD), 131 (LATTICE-UC), and 38 (IM011-127) patients were randomized. The primary endpoints were not met for all three studies, which resulted in early study termination for LATTICE-CD and IM011-127. High efficacy rates were observed in placebo groups throughout the studies. In all studies, the safety profile of deucravacitinib was consistent with the known safety profile observed in patients with psoriasis, and no new safety signals were observed. Deucravacitinib at multiple doses did not demonstrate significant clinical benefit vs placebo in moderately to severely active Crohn's disease or ulcerative colitis. Deucravacitinib was safe and well-tolerated.

Effects of probiotic and vitamin D co-supplementation on migraine index, quality of life, and oxidative stress in adults with migraine headache: a randomized triple-blinded clinical trial.

The current study was conducted to assess the effect of probiotic and vitamin D co-supplementation on migraine index (MI), migraine-specific quality of life (MSQoL), and oxidative stress in adults with migraine. This parallel randomized, triple-blinded, placebo-controlled trial was conducted among adult individuals aged 18 to 55 years with a diagnosis of migraine headache according to the International Classification of Headache Disorders-3 (ICHD-3). Patients were randomized to either multispecies probiotic (4.5 × 1011 CFU per day) plus vitamin D (50,000 IU every two weeks) or placebo for 12 weeks. MI, MSQoL, blood pressure, anthropometric, and biochemical variables (25-hydroxy vitamin D, nitric oxide (NO), malondialdehyde (MDA), total oxidative status (TOS), total antioxidant capacity (TAC), and catalase (CAT)) were examined at baseline and after 12 weeks of intervention. In total, 72 patients (36 patients in each group) with migraine headache were included in the study. The mean age of patients was 37.46 ± 0.98 and sixty five out of 72 patients were females. A significant increase in mean serum levels of 25-hydroxy vitamin D was observed in the probiotic plus vitamin D group compared to the placebo group (p < 0.001). A significantly greater reduction in mean MI (-30.11 ± 6.95 vs. -11.97 ± 3.05; p = 0.01) was found in the probiotic plus vitamin D than in the placebo group. In addition, a marginally significant difference was observed between the two groups regarding changes in serum levels of NO (p = 0.05). This trial showed that probiotic plus vitamin D supplementation can favorably improve MI as well as serum levels of NO in adult patients with migraine. Further research on mechanisms through which the supplementation was effective on MI is warranted.

Influence of serotonin on the long-term muscle contraction of the Kohnstamm phenomenon

Neuromodulation plays a central role in human movement control. An imbalance of neurotransmitters, especially dopamine and serotonin, can be associated with various neurological disorders causing tremors or spasms. Specifically, serotonin was shown to scale motoneuron excitability following intense muscle contractions, affecting short-latency reflexes. Likely, it may also influence motoneuron modulation in prolonged contractions, although this lacks experimental evidence. An intriguing test case for this hypothesis is presented by the Kohnstamm phenomenon, where sustained muscle contractions lead to prolonged amplified EMG activity and involuntary motions, aligning with the timescale of serotonergic amplification. The suspected serotonin influence on this effect was tested in a placebo-controlled human user study with 14 participants, where half were administered the serotonin antagonist Cyproheptadine and the other half a placebo. Comparing EMG and force responses after inducing the Kohnstamm phenomenon in the deltoid muscles revealed statistically significant faster EMG decay with the serotonin antagonist, while decay remained consistent in the placebo group compared to the response of the same participant group without medication. The force measurements showed the same trend, although no significance. This provides new data-based evidence that serotonin contributes to long-term motoneuron modulation, extending previous findings about the dedicated role and influence of this neurotransmitter. Additionally, the work suggests the phenomenon as an interesting test case to investigate the dedicated involvement of different neurocontrol mechanisms such as Persistent Inward Currents.

Probiotic reduces vaginal HPV abundance, improves immunity and quality of life in HPV-positive women: a randomised, placebo-controlled and double-blind study.

The Human Papillomavirus (HPV) is one of the main causes of cervical cancer in women, while there are currently no treatment nor intervention to reduce the concentration of cervical HPV. We thus aimed to investigate the effects of a probiotic Lactiplantibacillus plantarum Probio87 (orally administered at 9 log CFU/day) or placebo for 12-weeks, on reducing the abundance of vaginal HPV in HPV-positive women. A parallel, randomised, double-blind and placebo-controlled study was performed where women were randomised to either the probiotic (n= 44, mean age 41.70± 1.06 years) or placebo (n= 45, mean age 41.13± 1.20 years). After 12 weeks, the probiotic group showed reduced vaginal HPV abundance ( P = 0.001) and Nugent scores ( P < 0.001) as compared to the placebo. VAS and VuAS questionnaires showed that the probiotic group had improved vulvar dryness ( P = 0.023), soreness ( P = 0.049), social interactions, daily activities ( P < 0.05), and sexual activity ( P = 0.022) compared to the placebo group. Blood gene expressions showed that the placebo group had higher upregulation of pro-inflammatory cytokines (IL-1β, P = 0.006; IFN-γ, P = 0.028) and T-cell markers (CD44, P = 0.008; CXCR5, P = 0.040; CD4, P = 0.016) compared to the placebo group, indicating increased inflammation. Neurotrophic factors BDNF and CREB were upregulated in the placebo group ( P < 0.05), with higher IDO ( P = 0.001) and TDO ( P = 0.036) expressions compared to the probiotic group, suggesting increased kynurenine pathway activity and stress. Overall, probiotic supplementation appeared to reduce the abundance of vaginal HPV, possibly by lowering inflammation and enhancing immunity while mitigating the negative impacts of HPV infection on quality of life in HPV-positive women. Clinical trial registration: ClinicalTrials.gov (NCT05316064).

Benefit-Cost Analysis of Noninvasive Early Childhood Caries Interventions among Latvian Children.

Analyze the benefit-cost analysis of noninvasive early childhood caries (ECC) management in Latvian preschoolers versus placebo, from a health care perspective, over 12 mo. Randomized, blinded, placebo-controlled trial (September 2020-August 2022) at Riga Stradins University, Latvia. A factorial trial was conducted with 3 interventions (placebo, silver diamine fluoride [SDF], Tiefenfluorid) and 2 recall intervals (none: 1 and 6 mo: 2), all including behavioral modification. The 6 strategies were placebo (P1, P2), SDF (SDF1, SDF2), and Tiefenfluorid (TF1, TF2). Probabilistic sensitivity analysis was calculated from the health care perspective. Costs associated with each ECC management program and associated treatments were identified and measured. Incremental benefit-cost ratios (IBCRs) were calculated to determine the margin by which each program was more beneficial than P1 (comparator). The primary outcome measure used for economic evaluation was health care complications averted, defined as teeth with pulp involvement due to dental caries. The economic costs associated with health care complications averted were quantified in monetary terms as benefits. All alternative strategies were more effective than the comparator in averting health care complications and dental caries lesions. Over 12 mo, SDF2, TF2, and P2 were dominant interventions, yielding an IBCR of -0.98, -0.80, and -0.70, respectively. SDF1 and TF1 had an IBCR of 2.95 and 10.67, respectively, rending these interventions economically beneficial but with lower return on investment. Biannual SDF applications (SDF2) were the most cost-effective for ECC, significantly outperforming Tiefenfluorid® (TF2) and placebo (P2). TF2 and P2 slightly improved over placebo (P1) due to additional behavioral modification and counseling. Implementing SDF2 in Latvia would likely reduce health care complications and costs.Knowledge Transfer Statement:This study compared 5 noninvasive early childhood caries management strategies with a placebo "no treatment" group over a 12-mo period. The primary outcome measure was health care complications averted, quantified in monetary terms. The results showed that the 6-monthly applications of SDF and fluoride varnish demonstrated cost savings compared with the placebo group. The study recommends implementing SDF and fluoride varnish into routine clinical practice to reduce health care complications and associated costs.

Quantitative Muscle Magnetic Resonance Outcomes in Patients With Duchenne Muscular Dystrophy: An Exploratory Analysis From the EMBARK Randomized Clinical Trial.

Delandistrogene moxeparvovec is a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene transfer therapy for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed pathogenic variant of the DMD gene. In a subset of patients in the EMBARK (A Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of Delandistrogene Moxeparvovec [SRP-9001] in Participants With DMD) randomized clinical trial, changes in muscle health and pathology were assessed to evaluate the therapeutic impact of the treatment on disease progression. To determine the effect of delandistrogene moxeparvovec on muscle quantitative magnetic resonance (QMR) measures of disease progression in patients in the EMBARK trial. This was a phase 3, double-blind, placebo-controlled (October 2021-September 2023; week 52 cutoff date: September 13, 2023), multicenter randomized clinical trial that included 131 patients. Patients were randomized, and 125 were treated with either delandistrogene moxeparvovec (n = 63) or placebo (n = 62). The current study focused on a subset of patients who underwent muscle QMR imaging. Single-administration intravenous delandistrogene moxeparvovec (1.33 × 1014 vector genome/kg) or placebo. Change from baseline to week 52 in muscle MR was a prespecified exploratory end point. Proton MR spectroscopy (MRS) and 8-point Dixon MR imaging (MRI) measured muscle fat fraction (FF); multislice spin echo MRI measured transverse relaxation time (T2). MRS FF was measured in the soleus and vastus lateralis. MRI FF and T2 were measured in 5 leg muscle locations important for ambulation. A post hoc global statistical test combining all muscles and modalities assessed overall treatment effect. In this exploratory EMBARK analysis, 39 male participants (delandistrogene moxeparvovec, n = 19; placebo, n = 20; mean [SD] age, 6.10 [1.04] years; mean [SD] baseline North Star Ambulatory Assessment total score, 22.99 [3.71] points) underwent muscle MRI. Treated patients showed less disease progression vs placebo on MR measures. Across muscles and modalities, magnitudes of FF change favored delandistrogene moxeparvovec; between-group differences in least-squares mean change ranged from -1.01 (95% CI, -2.79 to 0.77; soleus) to -0.71 (95% CI, -3.21 to 1.80; vastus lateralis) for MRS FF and -3.09 (95% CI, -7.62 to 1.45; vastus lateralis) to -0.44 (95% CI, -4.01 to 3.12; hamstrings) for MRI FF. T2 reductions (improvements; 4 of 5 muscles) were observed in treated patients vs increases (worsening; all muscles) in placebo patients; within-group differences in least-squares mean change ranged from -1.06 (95% CI, -2.10 to -0.02; soleus) to 0.17 (95% CI, -1.76 to 2.10; biceps femoris) in the delandistrogene moxeparvovec group and from 1.12 (95% CI, 0.08-2.16; soleus) to 2.94 (95% CI, 0.84-5.03; quadriceps) in the placebo group. The global statistical test supported treatment benefit (P = .03). Results reveal that QMR outcomes consistently favored delandistrogene moxeparvovec across muscle groups, with treatment leading to decreased fat accumulation and improved T2 vs placebo over 52 weeks. Consistent with treatment effects on functional outcomes observed in the EMBARK trial, these results suggest stabilization or less progression of muscle pathology with delandistrogene moxeparvovec-adding to the totality of evidence supporting disease stabilization or slowing of disease progression with delandistrogene moxeparvovec. ClinicalTrials.gov Identifier: NCT05096221.

Darbepoetin, Red Cell Mass, and Neuroprotection in Preterm Infants: A Randomized Clinical Trial.

Previous studies suggest that administration of erythropoiesis-stimulating agents darbepoetin or erythropoietin to preterm infants results in fewer transfusions, fewer donor exposures, and improved neurodevelopmental outcome. To determine if, compared with placebo, preterm infants randomized to weekly darbepoetin would have greater red cell mass during hospitalization and better neurocognitive outcome at 22 to 26 months' corrected age. This randomized clinical trial was conducted between September 2017 and November 2019 for infants 23 0/7 to 28 6/7 weeks' gestation in 19 US Neonatal Research Network centers comprising 33 neonatal intensive care units. Follow-up occurred through January 2023. Infants were randomized by 36 hours after birth to weekly placebo or darbepoetin (10 μg/kg) through 35 weeks' postmenstrual age. Iron administration and transfusions were administered by protocol. Study data were analyzed from June to October 2023. The primary outcome was the mean cognitive composite score on the Bayley Scales of Infant Development, third edition (Bayley-III) at 22 to 26 months' corrected age. The lowest possible score (54) was assigned to infants who died. A total of 650 infants (322 darbepoetin; 328 placebo; mean [SD] gestational age, 26.2 [1.7] weeks; 328 female [50.5%]) were enrolled. Five hundred eighty-three infants (291 darbepoetin; 292 placebo) had the primary outcome determined (90% of those enrolled). Mean (SD) cognitive scores were similar between groups: 80.7 (19.5) darbepoetin vs 80.1 (18.7) placebo, adjusted mean difference, -0.23 (95% CI, -3.09 to 2.64). Compared with infants receiving placebo, more infants in the darbepoetin group were transfusion free (40% [127 of 319] vs 21% [70 of 327]; adjusted relative risk [RR], 1.3; 95% CI, 1.2-1.5), received fewer transfusions (mean [SD], 2.3 [3.1] vs 3.3 [3.5]), were exposed to fewer donors (mean [SD], 1.6 [2.3] vs 2.2 [2.3]), had higher red cell mass by week 2 of age (adjusted mean difference, 3.2; 95% CI, 1.7-4.7), and higher mean hematocrit by week 2 of age (adjusted mean difference, 2.8; 95% CI, 2.1-3.6), and were less likely to have bronchopulmonary dysplasia greater than grade 1 (35% [91 of 261] vs 46% [128 of 277]; RR, 0.78; 95% CI, 0.64-0.96). The incidence of retinopathy of prematurity stage greater than 2 was similar between groups, 13% (35 of 273) in the darbepoetin group vs 16% (45 of 279) in the placebo group. There were no differences in adverse effects between groups. Results of this randomized clinical trial reveal that this dose and dosing schedule of darbepoetin did not improve cognitive scores of preterm infants at 22 to 26 months' corrected age. Darbepoetin significantly increased red cell mass resulting in higher hematocrit values, fewer transfusions, and fewer donor exposures. ClinicalTrials.gov Identifier: NCT03169881.

Rizatriptan vs Placebo for Attacks of Vestibular Migraine: A Randomized Clinical Trial.

Vestibular migraine has no established treatments. To test the efficacy of rizatriptan for treating vestibular migraine attacks. This double-blind, randomized clinical trial of rizatriptan vs placebo was conducted from December 2014 through July 2020 (data analyses in 2021 and sensitivity analyses in 2022 and 2024) at 2 tertiary neurotologic centers. Adults with vestibular migraine were included. All participants underwent prospective observation to confirm diagnosis and illness activity and were then randomized in a 2:1 ratio to receive rizatriptan 10 mg or placebo to treat up to 3 vestibular migraine attacks per participant. Participants rated symptoms as absent, mild, moderate, or severe at scheduled intervals. Primary outcomes were the percentage of attacks with reductions in vertigo and unsteadiness/dizziness from moderate or severe to absent or mild at 1 hour. Secondary outcomes were the percentage of attacks with complete resolution of vestibular symptoms at 1 hour; reductions in headache and associated symptoms at 1 hour; use of rescue medications after 1 hour; reductions in vestibular, headache, and associated symptoms at 24 hours without rescue medications; treatment satisfaction and quality of life at 48 hours; and rates of serious adverse effects and discontinuation due to adverse effects. Of 222 total participants (mean [SD] age, 42.3 [11.7] years; 70.7% were women), 134 (60.4%) with active illness treated 307 attacks. Efficacy was tested using 240 attacks with vestibular symptoms rated as moderate or severe when participants took study drug. At 1 hour, rizatriptan did not differ from placebo for reducing vertigo (73/151 [48.3%] vs 50/88 [56.8%] attacks; odds ratio [OR], 0.71 [95% CI, 0.42-1.21]), unsteadiness/dizziness (29/151 [19.2%] vs 11/89 [12.4%] attacks; OR, 1.69 [95% CI, 0.80-3.57]), or any secondary outcomes. Similar percentages of participants in rizatriptan and placebo groups (26.4% for both groups) added rescue remedies after 1 hour. At 24 hours, rizatriptan had medium effects over placebo for unsteadiness/dizziness (OR, 2.65) and motion sensitivity (OR, 3.58). Post hoc analyses of all treated attacks found a medium effect favoring rizatriptan for headache and photophobia or phonophobia at 24 hours. Treatment satisfaction was equivocal. Quality of life was mixed. No participants experienced serious adverse effects or discontinued treatment for adverse effects. In this study, rizatriptan was ineffective at 1 hour for treating vestibular migraine attacks and had limited benefit on symptoms at 24 hours. Findings do not support using rizatriptan for vestibular migraine attacks. ClinicalTrials.gov Identifier: NCT02447991.

The Efficacy and Safety of BCD-180, an Anti-TRBV9+ T cell Monoclonal Antibody, in Patients with Active Radiographic Axial Spondyloarthritis: 36-week Results from the Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study ELEFTA.

. Two hundred sixty patients with active r-axSpA and inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) were randomized into three groups to receive either seniprutug (BCD-180) 5 or 7 mg/kg, or placebo. BCD-180 was administered in the respective group dose using a 0-12-36 week regimen. The placebo group patients were switched to BCD-180 5 mg/kg at Week 24, with therapy continued at Week 36. The primary endpoint was the proportion of patients achieving 40% improvement in the Assessment in Spondyloarthritis International Society (ASAS40) score at Week 24. The secondary endpoints included the proportion of patients achieving an ASAS20/40 response, improvement in 5 of 6 ASAS criteria (ASAS5/6), partial remission according to ASAS, ASDAS-CRP clinically important improvement in (Ankylosing Spondylitis Disease Activity Score with C-reactive protein level, ASDAS-CII) and ASDAS-CRP major improvement (ASDAS-MI). An analysis of changes over time in the disease activity status according to ASDAS-CRP, BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) scores, as well as changes over time in laboratory markers (CRP and erythrocyte sedimentation rate (ESR)) was also conducted. Safety was assessed based on the frequency and profile of adverse events (AE) and adverse reactions (AR). : The proportion of patients who achieved an ASAS40 response at Week 24 on seniprutug (BCD-180) at doses of 7 and 5 mg/kg was 51.4 and 40.8%, respectively, compared with 24% in the Placebo group (p = 0.0012 and p = 0.0417, respectively). Analysis of secondary endpoints showed that the efficacy of BCD-180 at both study doses was statistically significantly superior to placebo in patients with r-axSpA at Week 24 in the following respects: reduction in the proportion of subjects with very high disease activity (ASDAS-CRP > 3.5), achieving ASDAS-CII, ASAS20, ASAS5/6 response. A statistically significant decrease in the ASDAS-CRP, BASDAI, BASFI score, as well as CRP and ESR levels was demonstrated. Tolerability of seniprutug therapy was assessed as acceptable. The most common AEs were infusion-related reactions, most of which were mild to moderate according to CTCAE 5.0 (Common Terminology Criteria for Adverse Events) and developed mainly during the first administration. The proportion of patients with detected binding antibodies was 5.1%. No neutralizing antibodies were detected. . Seniprutug (BCD-180) as a therapy for r-axSpA has demonstrated superiority over placebo in the clinical efficacy, a good safety profile and low immunogenicity.

ИССЛЕДОВАНИЕ БЕЗОПАСНОСТИ И ТЕРАПЕВТИЧЕСКОГО ПОТЕНЦИАЛА УРСОДЕЗОКСИХОЛЕВОЙ КИСЛОТЫ ПРИ БОЛЕЗНИ ПАРКИНСОНА

Goal. To evaluate the safety and therapeutic potential of ursodeoxycholic acid (UDCA) in patients with Parkinson's disease and to study its effect on the progression of the disease. Materials and methods. In a study conducted at the Republican Clinical Hospital in Makhachkala from January 2023 to October 2024, 10 participants with Parkinson's disease received UDCA at a dosage of 30 mg/kg for 48 weeks, followed by an 8-week withdrawal period. The participants were divided into the main treatment and placebo groups in a 2:1 ratio. Safety, tolerability, and treatment adherence were evaluated, along with changes in bioenergetic brain metabolites, gait analysis, and MDS-UPDRS-III. Results. UDCA demonstrated a positive effect on the bioenergetic profile of the midbrain, manifested in a decrease in ΔGATP and an increase in Pi levels. Changes in gait parameters also indicated improvement, although clinical improvement remained moderate. UDCA has shown a high safety profile and good tolerability, with few temporary side effects. Conclusions. UDCA has the potential to improve metabolic and motor performance in patients with Parkinson's disease. More extensive research is needed to confirm these results. Given its safety and beneficial effects on mitochondrial functions, UDCA deserves further study as part of a comprehensive therapy to slow the progression of the disease and improve quality of life.

From Gut to Skeletal Muscle: Synergistic Effects of Probiotics and Spirulina Supplementation on Soccer Players' Performance and Body Composition.

Nutritional strategies are critical for optimizing soccer players' performance and body composition. Spirulina, a protein-rich plant-based supplement, and probiotics offer individual benefits. However, their combined effects remain underexplored. This study investigated the effects of co-supplementation with spirulina and probiotics on body composition, isokinetic, isometric strength, and performance metrics in male soccer players. In a double-blind, placebo-controlled trial, forty soccer players were randomly assigned to four groups: placebo (PLA), probiotics (PRO), spirulina (SPI), and combined probiotics-spirulina (PRO + SPI). The PRO group received two probiotic capsules (a total dose of 4.5 × 1011CFU) daily, with breakfast and dinner. The SPI group consumed two 1-g spirulina tablets twice daily (2g total), with breakfast and dinner. The PRO + SPI group received both supplements in the same dosing regimen, while the PLA group consumed starch-based placebo capsules. Over eight weeks, participants followed identical training regimens. Pre- and post-intervention assessments included body composition (weight, BMI, fat percentage, fat weight, muscle weight), performance metrics (vertical jump, agility, speed, anaerobic sprint tests), and isokinetic and isometric knee strength tests. Statistical analyses utilized repeated measures and Bonferroni post-hoc tests. The PRO + SPI group demonstrated more significant reductions in weight (P = 0.012) and fat weight (P = 0.001) compared to the PLA group, while the SPI group showed a significant reduction in fat percentage (P = 0.034). Agility scores improved significantly in the PRO + SPI group compared to the PLA (P = 0.001) and SPI (P = 0.004) groups. Isokinetic performance metrics, including average power during knee extension at 60°/s and 180°/s, improved significantly in the PRO + SPI group compared to the PLA group (P = 0.018 and P = 0.009, respectively). Similarly, the PRO and SPI groups outperformed the PLA group in isokinetic measures such as absolute peak torque at 60°/s (P = 0.032) and 180°/s (P = 0.006). Also, maximum voluntary isometric contraction (MVIC) improved significantly in the PRO and SPI groups compared to the PLA group (P = 0.001 for both). From gut to skeletal muscle, spirulina, and probiotic co-supplementation significantly enhanced body composition, reduced weight and fat mass, and improved agility and isokinetic strength compared to placebo or individual supplementation. These results emphasize the synergistic potential of this nutritional strategy for optimizing athletic performance and recovery, warranting further investigation across diverse athletic populations.

Effect of Bacillus coagulans BC99 supplementation on body weight and gut microbiota in overweight and obese individual: a randomized, double-blind, placebo-controlled study

IntroductionProbiotic supplementation is a safe and effective way to reduce overweight and obesity by regulating the gut microbiota. The Bacillus coagulans strain BC99 is derived from humans and has various probiotic-related, acid resistance, bile salt resistance, and adhesion-related domains in the genome. This study aimed to assess the effects of BC99 on the gut microbiota, body weight and lipid profiles of overweight and obese individuals.MethodsA total of 66 adult individuals were randomly assigned to a probiotic group (supplemented with 5 × 109 colony-forming units of BC99 per day along with 3 g of maltodextrin) and placebo group (supplemented with 3 g of maltodextrin daily) in a 1:1 ratio.ResultsAfter 8 weeks of oral administration, BC99 intervention significantly decreased the body weight of overweight individual (P &amp;lt; 0.01). Weight loss was significantly greater in the probiotic group than in the placebo group (P &amp;lt; 0.05). No significant differences were observed in lipid profiles between two groups. The microbiota analysis revealed that BC99 intervention significantly improved the β-diversity at week 4. The genus Parabacteroides was negatively correlated with body weight and was found to be enriched in the BC99 group.DiscussionThese findings suggest that B. coagulans strain BC99 could be a beneficial candidate for modulating the gut microbiota and improve body weight management for overweight individuals.Clinical trial registrationClinicalTrials.gov, identifier NCT06077383.

Efruxifermin in Compensated Liver Cirrhosis Caused by MASH.

In phase 2 trials involving patients with stage 2 or 3 fibrosis caused by metabolic dysfunction-associated steatohepatitis (MASH), efruxifermin, a bivalent fibroblast growth factor 21 (FGF21) analogue, reduced fibrosis and resolved MASH. Data are needed on the efficacy and safety of efruxifermin in patients with compensated cirrhosis (stage 4 fibrosis) caused by MASH. In this phase 2b, randomized, placebo-controlled, double-blind trial, we assigned patients with MASH who had biopsy-confirmed compensated cirrhosis (stage 4 fibrosis) to receive subcutaneous efruxifermin (at a dose of 28 mg or 50 mg once daily) or placebo. The primary outcome was a reduction of at least one stage of fibrosis without worsening of MASH at week 36. Secondary outcomes included the same criterion at week 96. A total of 181 patients underwent randomization and received at least one dose of efruxifermin or placebo. Of these patients, liver biopsy was performed in 154 patients at 36 weeks and in 134 patients at 96 weeks. At 36 weeks, a reduction in fibrosis without worsening of MASH occurred in 8 of 61 patients (13%) in the placebo group, in 10 of 57 patients (18%) in the 28-mg efruxifermin group (difference from placebo after adjustment for stratification factors, 3 percentage points; 95% confidence interval [CI], -11 to 17; P = 0.62), and in 12 of 63 patients (19%) in the 50-mg efruxifermin group (difference from placebo, 4 percentage points; 95% CI, -10 to 18; P = 0.52). At week 96, a reduction in fibrosis without worsening of MASH occurred in 7 of 61 patients (11%) in the placebo group, in 12 of 57 patients (21%) in the 28-mg efruxifermin group (difference from placebo, 10 percentage points; 95% CI, -4 to 24), and in 18 of 63 patients (29%) in the 50-mg efruxifermin group (difference from placebo, 16 percentage points; 95% CI, 2 to 30). Gastrointestinal adverse events were more common with efruxifermin; most events were mild or moderate. In patients with compensated cirrhosis caused by MASH, efruxifermin did not significantly reduce fibrosis at 36 weeks. (Funded by Akero Therapeutics; SYMMETRY ClinicalTrials.gov number, NCT05039450.).

Effects of phototherapy combined with Lactobacillus salivarius AP-32 or Bifidobacterium animalis subsp. lactis CP-9 on improving neonatal jaundice and gut microbiome health: a randomized double-blind clinical study

Neonatal jaundice is a common condition observed in newborns shortly after birth, making it one of the most frequent health concerns during the first two weeks of life. This study, conducted between May 2019 and July 2023, enrolled 300 full-term infants with bilirubin levels exceeding 15 mg/dL on the fourth day after birth. The infants were recruited and randomly assigned in equal numbers to one of three groups for further investigation. In addition to the control group, the other two groups of infants received probiotic supplementation administered twice daily, with each capsule delivering 5 × 10⁹ CFU of either Lactobacillus salivarius AP-32 or Bifidobacterium animalis subsp. lactis CP-9. Both probiotic groups significantly reduced the overall duration of phototherapy and accelerated the rate of bilirubin reduction compared to the control group. The AP-32 group experienced a significant reduction in hospitalization duration, staying seven hours less than the placebo group (P = 0.024). Analysis of gut microbiota revealed that the probiotic groups significantly enhanced microbial diversity in the intestines of neonates. The AP-32 group showed a significant increase in the abundance of L. salivarius, while the CP-9 group demonstrated a notable enhancement in the abundance of B. animalis. These findings suggest that integrating phototherapy with probiotic supplementation may enhance jaundice clearance increasing the abundance of beneficial gut bacteria, thereby facilitating the recovery of neonates.