Placebo In Adults Research Articles

413 Improvement in itch, symptoms and quality of life with upadacitinib through week 16 in adults and adolescents with atopic dermatitis: results from phase 3 studies (Measure Up 1, Measure Up 2 and AD Up)

Abstract Atopic dermatitis (AD) is characterized by intense itch and symptoms that adversely impact quality of life (QoL). Upadacitinib is a selective Janus kinase-1 inhibitor approved for moderate-to-severe AD. We assessed the effect of once daily oral upadacitinib (15 or 30 mg), with or without concurrent topical corticosteroid treatment, on patient-reported outcomes for adults and adolescents with moderate-to-severe atopic dermatitis during the double-blind, placebo-controlled phase 3 clinical trials, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422) and AD Up (NCT03568318). Assessments included itch (Worst Pruritus Numerical Rating Scale), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient Oriented Eczema Measure) and sleep, daily activities and emotional state (AD Impact Scale). Post hoc analysis of 2240 adults and 344 adolescents randomized patients was performed. By Week 2, more patients receiving upadacitinib achieved a clinically relevant response in itch, skin pain, symptom severity, symptom frequency, sleep, daily activities and emotional state vs. placebo across studies among adults (upadacitinib 15 mg: 30.8–87.3%; upadacitinib 30 mg: 38.0–89.9%; placebo: 2.1–43.1%; nominal P < 0.001 for all comparisons) and adolescents (upadacitinib 15 mg: 19.4–82.9%; upadacitinib 30 mg: 35.3–97.6%; placebo: 0–41.0%; nominal P < 0.05 for 37/42 comparisons). These trends continued through week 16 where response rates for all outcomes improved with upadacitinib vs. placebo in adults (upadacitinib 15 mg: 42.9–80.4%; upadacitinib 30 mg: 60.9–84.6%; placebo: 10.1–38.1%; nominal P < 0.001 for all comparisons) and adolescents (upadacitinib 15 mg: 33.3–78.0%; upadacitinib 30 mg: 50.0–85.7%; placebo: 2.8–43.6%; nominal P < 0.05 for 41/42 comparisons). These findings highlight the rapid, sustained efficacy of once daily oral upadacitinib in improving symptom burden and QoL in adults and adolescents with moderate-to-severe AD.

399 Pooled safety analysis of lebrikizumab in patients with uncontrolled asthma from three randomized clinical trials

Abstract LAVOLTA (L)I, LII and ACOUSTICS were randomized, placebo-controlled, double-blinded, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting interleukin-13, in patients with uncontrolled asthma (LI, NCT01867125; LII, NCT01868061; ACOUSTICS, NCT01875003). These studies failed to provide consistently significant efficacy results in uncontrolled asthma. This study aims to report pooled safety analysis of lebrikizumab in patients during the 52-week placebo-controlled period from the three clinical trials. Adults in LI and LII, adolescents (12–17 years) in ACOUSTICS, with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40–90% predicted and stable background therapy were randomized 1 : 1 : 1 to lebrikizumab 125 or 37·5 mg or placebo (PBO) subcutaneously once every 4 weeks. Safety analyses were based on all patients who received at least one dose of study drug, with patients grouped by assigned treatment. Safety was assessed using summary of adverse events (AEs). The proportions of patients who experienced treatment-emergent AEs [combined lebrikizumab doses (LEB), 1281 (77%) of 1661 patients vs. PBO, 650 (78%) of 883 patients], serious AEs (7.6% vs. 8.5%) and AEs leading to study drug discontinuation (3.4% vs. 3.6%) were similar between LEB and PBO. One death occurred in the PBO group. Similar frequencies of key safety events, including conjunctivitis (LEB, 1.6%; PBO, 1.7%), infections and infestations (LEB, 51.6%; PBO, 50.7%), and eosinophil-related disorders (LEB, 0.2%; PBO, 0.2%) were noted; higher frequency of eosinophilia (>500 eosinophils/mm3) was reported (LEB, 1.1%; PBO, 0%). The safety profile was similar between lebrikizumab and placebo in adults and adolescents with uncontrolled asthma.

#4341 ASSIST STUDY DESIGN: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSSOVER STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY (IGAN) ON SGLT2I

Abstract Background and Aims IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis. Approximately 30-45% of IgAN patients progress to ESKD over a period of 20-25 years and proteinuria is the strongest predictor of disease progression. Endothelin A (ETA) receptor activation drives proteinuria, kidney inflammation and fibrosis. Atrasentan, a potent and selective ETA antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. Interim results of a phase 2, open-label study in patients with IgAN (AFFINITY, NCT04573920) demonstrated that atrasentan was well tolerated and resulted in clinically meaningful and sustained proteinuria reductions in patients receiving a maximally tolerated and optimized dose of a RAS inhibitor (RASi; Kim et al. 2022, ASN Kidney Week FC052). Sodium glucose cotransporter-2 inhibitors (SGLT2is) are approved for use in adults with CKD at risk of kidney disease progression. In a post-hoc analysis of a global phase 3 study in patients with type 2 diabetes and CKD (SONAR), 6 week treatment with SGLT2i and atrasentan (n = 14) resulted in greater reductions in albuminuria (change in UACR from baseline −54.7%, 95%CI −64.6 to −42.0) compared to atrasentan alone (change in UACR from baseline −37.6%, 95%CI −45.9 to −28.0), suggesting independent and additive effects of both drug classes (Heerspink et al. 2021, Kidney Intl). The ASSIST study will evaluate the safety and efficacy of atrasentan vs. placebo in adults with IgAN and persistent proteinuria while on stable background SGLT2i and RASi therapy. Methods The ASSIST trial is a randomized, double-blind, placebo-controlled, crossover clinical trial. Approximately 52 patients with biopsy-proven IgAN and eGFR ≥ 30 mL/min/1.73 m2 (CKD-epi) who are receiving maximally tolerated RASi for at least 12 weeks prior to screening will be enrolled. Patients on a stable dose of SGLT2i prior to screening (SGLT2i stable) must have total urine protein of >0.5 grams/day at screening. Patients who are not currently on SGLT2i or are not on a stable dose of SGLT2i must have a total urine protein of >0.85 grams/day at screening and enter a run-in period during which they receive SGLT2i for 8 weeks (SGLT2i run-in), after which they must have a total urine protein of >0.5 grams/day confirmed at the Week-1 visit (Figure). Choice of SGLT2i will be at the discretion of the principal investigator and per local treatment standards. Thereafter, all eligible patients will be randomized 1:1 to sequence AB or sequence BA in which they will receive 0.75 mg atrasentan once daily (QD) during one period and placebo during the other period. Randomization will be stratified by SGLT2i status (stable vs run-in). All subjects will enter Treatment Period 1 for 12 weeks, followed by a 12-week washout period, and then Treatment Period 2 for 24 weeks. Following the end of treatment, patients will have follow-up evaluations for safety approximately 4 weeks after the end of treatment. Fifty-two subjects will provide approximately 83% power using a two-sided pairwise test (α 0.05) to detect a treatment effect of at least 0.288 in natural log transformed UPCR (25% reduction) between atrasentan and placebo. Results Primary and secondary endpoints are change in proteinuria (UPCR from 24-hr collection) from baseline to week 12 and week 24, respectively. Type, incidence, severity, seriousness, and relatedness of adverse events will be evaluated. Change in eGFR from baseline to week 24 in Treatment Period 2 will be evaluated as an exploratory endpoint. Conclusion Atrasentan is a potent and selective ETA antagonist. Interim results from the AFFINITY Phase 2 open-label study demonstrated that atrasentan resulted in sustained, clinically meaningful reductions in proteinuria in patients with IgAN. The phase 2 ASSIST study will examine the effects of atrasentan in combination with SGLT2i in patients with IgAN who are also receiving maximally tolerated RASi.

THE EFFECT OF SEMAGLUTIDE ON BLOOD PRESSURE IN PATIENTS WITHOUT DIABETES: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective: The interplay of hypertension and obesity is well described. Recent advances in the pharmacological treatment of obesity with glucagon-like peptide-1 receptor agonists (GLP-1 RA) highlight the potential to target excess body weight to improve blood pressure (BP). The aim of this review is to determine the BP reduction in trials of semaglutide for weight reduction in patients without diabetes. Design and method: This systematic review was performed in line with the 2020 PRISMA statement. Relevant studies were identified via a search of MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science. Studies were screened to include randomised controlled trials of semaglutide versus a placebo in adults without diabetes. Continuation of anti-hypertensive treatment was a secondary outcome. Pooled and sensitivity analyses were performed and risk of bias was assessed. Results: 611 potential studies were found by the search and 6 RCTs, with 4744 participants, were included in the final analysis. At baseline, the cohorts in these studies had a mean BP in the normotensive range. The mean difference in SBP was -4.83 mmHg (95% CI -5.65 to -4.02) while that for DBP was -2.45 mmHg (95% CI -3.65 to -1.24). Only two studies (STEP 1, 4) reported change in anti-hypertensive medications. In STEP 1, 34.3% of those on anti-hypertensive medications, and receiving the intervention, either decreased or stopped these drugs, versus 16% in the placebo group. Equivalent figures were 25.5% and 11.9% for STEP 4. Critical appraisal revealed all included studies to be of a high methodological quality. Conclusions: The magnitude of BP reduction evident following semaglutide treatment in normotensive populations with obesity and without diabetes is clinically significant. The effect of semaglutide in those with obesity and hypertension is yet to be determined. Targeting excess body weight may be a novel therapeutic strategy for patients with difficult to control hypertension.

Tumor volume and T2 hyperintensity changes from DeFi: A phase 3, randomized, controlled trial of nirogacestat in patients with desmoid tumors.

11514 Background: MRI tumor volume or T2 signal intensity changes may represent novel imaging techniques that could have a prognostic or predictive value for assessing response in desmoid tumors (DT). For example, hyperintense areas on T2-weighted images have been associated with active fibroblastic proliferation and ≥90% hyperintensity is associated with DT disease progression, whereas iso- or hypo-intense areas are associated with inactive sites of disease. In DeFi (NCT03785964), the novel gamma secretase inhibitor nirogacestat (n=70 patients) significantly improved the primary endpoint of PFS compared with placebo (n=72 patients; hazard ratio, 0.29 [95% CI, 0.15, 0.55; P<0.001]) and significantly improved the secondary endpoint of ORR per blinded, independent central review (41% vs 8%; P<0.001). Complete responses were achieved in 7% with nirogacestat and 0% with placebo. Here, we present an exploratory analysis of MRI tumor volume and T2 signal intensity changes in DeFi. Methods: Eligible adults had histologically confirmed DT that had progressed ≥20% per RECIST v1.1 within 12 months of screening. Patients were randomized 1:1 to receive nirogacestat 150 mg or placebo twice daily taken continuously in 28-day cycles. Volumetric MRI and T2 hyperintensity of the largest target tumor were evaluated at screening and every 6 cycles during the double-blind phase. MRI T2 signal intensity is represented as the ratio of hyperintensity in total tumor volume to muscle background. A blinded, independent, central radiologist reviewed all MRI scans. Results: Nirogacestat treatment led to more substantial reductions versus placebo in tumor volume and T2 hyperintensity ratio (Table). At baseline, similar proportions of patients in each arm had a T2 hyperintensity ratio ≥90% (95% vs 97%). This ratio changed from ≥90% at baseline to <90% at any time after baseline in 34% of patients in the nirogacestat arm and 15% of those on placebo. Conclusions: In DeFi, nirogacestat demonstrated substantial reduction of tumor volume and T2 hyperintensity of the largest target tumors by MRI compared with placebo in adults with DT. These results are consistent with the significant improvement in ORR achieved with nirogacestat. These data suggest that volumetric MRI and T2 hyperintensity might provide additional information in the evaluation of treatment response in DT. The prognostic or predictive value of these imaging techniques in DT should be further studied. Clinical trial information: NCT03785964 . [Table: see text]

Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes: a Phase I/II randomised double-blind placebo-controlled trial

Aim/hypothesisThis study aimed to investigate the safety and efficacy of treatment with allogeneic Wharton’s jelly-derived mesenchymal stromal cells (MSCs) in recent-onset type 1 diabetes.MethodsA combined Phase I/II trial, composed of a dose escalation followed by a randomised double-blind placebo-controlled study in parallel design, was performed in which treatment with allogeneic MSCs produced as an advanced therapy medicinal product (ProTrans) was compared with placebo in adults with newly diagnosed type 1 diabetes. Inclusion criteria were a diagnosis of type 1 diabetes <2 years before enrolment, age 18–40 years and a fasting plasma C-peptide concentration >0.12 nmol/l. Randomisation was performed with a web-based randomisation system, with a randomisation code created prior to the start of the study. The randomisation was made in blocks, with participants randomised to ProTrans or placebo treatment. Randomisation envelopes were kept at the clinic in a locked room, with study staff opening the envelopes at the baseline visits. All participants and study personnel were blinded to group assignment. The study was conducted at Karolinska University Hospital, Stockholm, Sweden.ResultsThree participants were included in each dose cohort during the first part of the study. Fifteen participants were randomised in the second part of the study, with ten participants assigned to ProTrans treatment and five to placebo. All participants were analysed for the primary and secondary outcomes. No serious adverse events related to treatment were observed and, overall, few adverse events (mainly mild upper respiratory tract infections) were reported in the active treatment and placebo arms. The primary efficacy endpoint was defined as Δ-change in C-peptide AUC for a mixed meal tolerance test at 1 year following ProTrans/placebo infusion compared with baseline performance prior to treatment. C-peptide levels in placebo-treated individuals declined by 47%, whereas those in ProTrans-treated individuals declined by only 10% (p<0.05). Similarly, insulin requirements increased in placebo-treated individuals by a median of 10 U/day, whereas insulin needs of ProTrans-treated individuals did not change over the follow-up period of 12 months (p<0.05).Conclusions/interpretationThis study suggests that allogeneic Wharton’s jelly-derived MSCs (ProTrans) is a safe treatment for recent-onset type 1 diabetes, with the potential to preserve beta cell function.Trial registrationClinicalTrials.gov NCT03406585FundingThe sponsor of the clinical trial is NextCell Pharma AB, Stockholm, Sweden.Graphical

Ravulizumab: A Review in Generalised Myasthenia Gravis.

Ravulizumab (ULTOMIRIS®) is the first long-acting complement C5 inhibitor (administered intravenously every 8 weeks) to be approved in several countries globally, for adults with generalised myasthenia gravis (gMG) who are anti-acetylcholine receptor antibody-positive (AChR Ab+). In the phase III CHAMPION MG trial, intravenous ravulizumab was associated with statistically significant improvements in the MG-Activities of Daily Living scale at week 26 of treatment compared with placebo in adults with AChR Ab+ gMG. Improvements in the Quantitative MG scale total score were also statistically significantly higher in ravulizumab than placebo recipients. These improvements were sustained to week 26 of treatment. Ravulizumab was generally well tolerated; the most common treatment-emergent adverse events were headache, diarrhoea and nausea. Efficacy and tolerability data for up to 1 year from the ongoing open-label extension phase are consistent with those from the randomized, placebo-controlled phase; further results are awaited with interest. Thus, ravulizumab is an efficacious, generally well tolerated and convenient treatment option in adults with AChR Ab+ gMG, expanding the options available for gMG management.

Design of the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor Versus Placebo in Patients With Congenital Systemic Right Ventricle Heart Failure (PARACYS-RV) Trial

The presence of a systemic right ventricle (sRV) with biventricular physiology (biV) is associated with increased patient morbidity and mortality. To date, no pharmacologic therapy for heart failure has been proven effective for patients with systolic dysfunction of the sRV-biV. We designed a randomized, double-blind, placebo-controlled crossover trial to compare sacubitril/valsartan treatment to placebo in adults (aged ≥ 18 years) with moderate-to-severe sRV-biV dysfunction and New York Heart Association functional class II to III symptoms. Two primary efficacy endpoints are assessed in the trial: exercise capacity (submaximal exercise duration) and neurohormonal activation (N-terminal prohormone brain natriuretic peptide). Secondary objectives include assessing a change in the Kansas City Cardiomyopathy Questionnaire score and evaluating the safety and tolerance of sacubitril/valsartan. A 6-week open run-in phase identifies the maximum tolerated dose of sacubitril/valsartan, up to 97 mg/103 mg twice daily. After a 2-week washout period, patients are randomized 1:1 to sacubitril/valsartan treatment vs placebo for a 24-week phase, followed by another 2-week washout period and subsequent crossover to the alternative treatment arm for an additional 24-week phase. Data to assess primary and secondary endpoints are collected at baseline and at the end of each phase. A total of 48 patients is required to provide > 80% power to detect a 30% difference in distance walked and in N-terminal prohormone brain natriuretic peptide levels with sacubitril/valsartan treatment vs placebo, each with a 2-sided P-value of 0.025. In summary, the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor vs Placebo in Patients With Congenital Systemic Right Ventricular Heart Failure Trial (PARACYS-RV) should determine the role of sacubitril/valsartan in treating heart failure in patients with sRV-biV and carries the potential to alter management of this patient population.

Consistency of Response to Liquid Celecoxib in Adults With Migraine: Post Hoc Analysis of Results From Two Randomized, Placebo-Controlled Studies (P13-12.005)

Consistency of Response to Liquid Celecoxib in Adults With Migraine: Post Hoc Analysis of Results From Two Randomized, Placebo-Controlled Studies (P13-12.005)

The Effect of Semaglutide on Blood Pressure in Patients without Diabetes: A Systematic Review and Meta-Analysis.

(1) Background: Recent advances in the pharmacological treatment of obesity with glucagon-like peptide-1 receptor agonists (GLP-1 RA) highlight the potential to target excess body weight to improve blood pressure (BP). This review aimed to determine the BP reduction in trials of semaglutide for weight reduction in patients without diabetes. (2) Methods: Relevant studies were identified via a search of research databases. Studies were screened to include randomized controlled trials (RCTs) of semaglutide versus a placebo in adults. Pooled and sensitivity analyses were performed, and risk of bias was assessed. (3) Results: six RCTs, with 4744 participants, were included in the final analysis. At baseline, the cohorts in these studies had a mean BP in the normotensive range. The mean difference in systolic BP was -4.83 mmHg (95% CI: -5.65 to -4.02), while that for diastolic BP was -2.45 mmHg (95% CI: -3.65 to -1.24). All included studies were of a high methodological quality. (4) Conclusions: A clinically significant reduction in BP was evident following semaglutide treatment in normotensive populations without diabetes. The effect of semaglutide in those with obesity and hypertension is as yet undetermined. Targeting excess body weight may be a novel therapeutic strategy for these patients.

Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study.

Immune thrombocytopenia (ITP) is characterized by primarily autoantibody-mediated platelet destruction and impaired platelet production resulting in thrombocytopenia and an increased risk of bleeding. Other manifestations include increased risk of thrombosis and diminished quality of life. Current treatment approaches are directed toward lowering the rate of platelet destruction or stimulating platelet production to prevent bleeding. Rilzabrutinib is an oral, reversible, potent Bruton tyrosine kinase inhibitor that was specifically designed to treat immune-mediated diseases and mediates its therapeutic effect through a dual mechanism of action: (1) inhibiting B-cell activation and (2) interrupting antibody-coated cell phagocytosis by Fc gamma receptor in spleen and liver. A 24-week dose-finding phase I/II study of rilzabrutinib in patients with ITP showed a 40% platelet response (⩾2 consecutive platelet counts of ⩾50 × 109/L and increase from baseline ⩾20 × 109/L without rescue medication use) and a well-tolerated safety profile with only grade 1/2 transient adverse events across dose levels. Assess the efficacy and safety of oral rilzabrutinib in adult and adolescent patients with persistent or chronic ITP. Rilzabrutinib 400 mg BID is being evaluated in the ongoing LUNA 3 multicenter, double-blind, placebo-controlled phase III study. The primary endpoint is durable platelet response, defined as achieving platelet counts of ⩾50 × 109/L for at least two-thirds of ⩾8 available weekly scheduled platelet measurements during the last 12 weeks (including ⩾2 available measurements within the last 6 weeks) of the 24-week blinded treatment period in the absence of rescue therapy. Ethical guidelines and informed consent are followed. The LUNA 3 trial will further investigate rilzabrutinib's safety and efficacy in adult and adolescent patients, with the primary goal of addressing a major objective in treating patients with ITP: durability of platelet response. ClinicalTrials.gov NCT04562766: https://clinicaltrials.gov/ct2/show/NCT04562766; EU Clinical Trials Register EudraCT 2020-002063-60: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60.

The efficacy of N-acetylcysteine in chronic obstructive pulmonary disease patients: a meta-analysis.

N-acetylcysteine (NAC) may reduce acute exacerbations of chronic obstructive pulmonary disease through an antioxidant effect. Due to the heterogeneity in studies, the currently available data do not confirm the efficacy of oral NAC therapy in chronic obstructive pulmonary disease patients. We hypothesize that chronic obstructive pulmonary disease patients receiving regular oral NAC therapy do not achieve improved clinical outcomes. The purpose of this meta-analysis was to determine the efficacy of long-term oral NAC therapy in chronic obstructive pulmonary disease patients. The literature search was performed using the PubMed, Web of Science, and Cochrane Library databases to identify all included clinical studies. Studies were eligible for inclusion only if they directly compared the outcomes of NAC versus placebo in adults with chronic obstructive pulmonary disease between 1 January 2000 and 30 May 2022. All studies were included if they reported one or more of the following outcomes: number of patients with no acute exacerbations, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), St George's Respiratory Questionnaire score, glutathione level, and adverse events. Nine randomized controlled trials were included in the meta-analysis. There were 1061 patients in the NAC group and 1076 patients in the placebo group. The current meta-analysis provides evidence that the number of patients with no acute exacerbations (965 patients receiving NAC therapy, 979 control group patients), change in FEV1 (433 patients receiving NAC therapy, 447 control group patients), change in FVC (177 patients receiving NAC therapy, 180 control group patients), change in St George's Respiratory Questionnaire score (128 patients receiving NAC therapy, 131 control group patients), change in glutathione levels (38 patients receiving NAC therapy, 40 control group patients), and adverse events (832 patients receiving NAC therapy, 846 control group patients) were not significantly different between the two groups. NAC did not reduce the risk of acute exacerbation or ameliorate the decline in lung volume in chronic obstructive pulmonary disease patients.

The efficacy of tranexamic acid treatment with different time and doses for traumatic brain injury: a systematic review and meta-analysis

ObjectiveTranexamic acid (TXA) plays a significant role in the treatment of traumatic diseases. However, its effectiveness in patients with traumatic brain injury (TBI) seems to be contradictory, according to the recent publication of several meta-analyses. We aimed to determine the efficacy of TXA treatment at different times and doses for TBI treatment.MethodsPubMed, MEDLINE, EMBASE, Cochrane Library, and Google Scholar were searched for randomized controlled trials that compared TXA and a placebo in adults and adolescents (≥ 15 years of age) with TBI up to January 31, 2022. Two authors independently abstracted the data and assessed the quality of evidence.ResultsOf the identified 673 studies, 13 involving 18,675 patients met our inclusion criteria. TXA had no effect on mortality (risk ratio (RR) 0.99; 95% confidence interval (CI) 0.92–1.06), adverse events (RR 0.93, 95% Cl 0.76–1.14), severe TBI (Glasgow Coma Scale score from 3 to 8) (RR 0.99, 95% Cl 0.94–1.05), unfavorable Glasgow Outcome Scale (GOS < 4) (RR 0.96, 95% Cl 0.82–1.11), neurosurgical intervention (RR 1.11, 95% Cl 0.89–1.38), or rebleeding (RR 0.97, 95% Cl 0.82–1.16). TXA might reduce the mean hemorrhage volume on subsequent imaging (standardized mean difference, -0.35; 95% CI [-0.62, -0.08]).ConclusionTXA at different times and doses was associated with reduced mean bleeding but not with mortality, adverse events, neurosurgical intervention, and rebleeding. More research data is needed on different detection indexes and levels of TXA in patients with TBI, as compared to those not receiving TXA; although the prognostic outcome for all harm outcomes was not affected, the potential for harm was not ruled out.Trial registrationThe review protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD42022300484).

How does povidone iodine alone or with dexamethasone compare with placebo for adults with epidemic keratoconjunctivitis?

How does povidone iodine alone or with dexamethasone compare with placebo for adults with epidemic keratoconjunctivitis?

Efficacy and safety of fermented Prunus mume vinegar on fatigue improvement in adults with unexplained fatigue: A randomized controlled trial.

The accumulation of fatigue leads to reduced physical, emotional, psychological, and social functions. Fermented Prunus mume vinegar (PV) improves fatigue in animals; however, studies in humans have not been conducted. We aimed to examine the effects and safety of consuming fermented PV for 8 weeks on fatigue indices in adults with unexplained fatigue while considering the placebo effect. A randomized, double-blind, placebo-controlled trial was conducted in adults of >19 years, who were diagnosed with unexplained fatigue for at least 1 month. Eighty participants were randomly assigned to receive daily 70 mL of fermented PV (2.56 mg/g, chlorogenic acid, and 15.3 mg/g, citric acid) or a placebo for 8 weeks. At baseline and 4 and 8 weeks after treatment, the participants were visited for blood tests (liver enzyme, glucose, creatinine, lactate, malondialdehyde [MDA], and creatine kinase [CK]) and questionnaires (Fatigue Severity Scale [FSS], fatigue visual analog scale [VAS], Beck Depression Inventory [BDI], the Korean version of the Brief Encounter Psychosocial Instrument [BEPSI-K], EQ-5D-3L, and EQ-VAS]). Fermented PV supplementation for 8 weeks did not remarkably improve the fatigue indices when compared to placebo. Additionally, differences in fatigue VAS, BDI, BEPSI-K, EQ-5D-3L, EQ-VAS, lactate, CK, and MDA concentrations between the groups were not observed. However, FSS had positively correlated with fatigue VAS, BDI, and BEPSI-K, whereas it was negatively correlated with EQ-5D-3L and EQ-VAS at the baseline and 8 weeks. None of the participants reported adverse events. The efficacy of fermented PV did not exceed the efficacy of placebo in adults with unexplained fatigue. [ClinicalTrials.gov], identifier [NCT04319692].

Systematic review and meta-analysis of intravenous iron therapy for adults with non-anaemic iron deficiency: An abridged Cochrane review.

Iron is an essential nutrient for oxygen supply and aerobic metabolism. Iron deficiency impacts cellular respiration and mitochondrial energy metabolism, which can lead to reduced skeletal muscle function and muscle mass, causing sarcopenia. Intravenous iron offers the ability to rapidly correct iron deficiency, but the functional impact on patient mental and physical health is unclear. We assessed the effects of intravenous iron therapy on physical function and quality of life in the treatment of adults with non-anaemic iron deficiency. An update and reanalysis of a previously published Cochrane systematic review was performed to assess randomized controlled trials that compared any intravenous iron preparation with placebo in adults. The primary functional outcome measure was physical performance as defined by the trial authors. Secondary outcome measures included fatigue and quality-of-life scores, and adverse effects at the end of follow-up. Biochemical efficacy was assessed by change in serum ferritin and haemoglobin concentration levels. Twenty-one randomized controlled trials, comprising 3514 participants, were included. Intravenous iron compared with placebo resulted in significantly increased physical function measured by mean peak oxygen consumption (mean difference [MD] 1.77mL/kg/min, 95% confidence interval [CI] 0.57 to 2.97). An overall improvement in fatigue was seen (standardized MD 0.30, 95% CI -0.52 to -0.09) but no overall difference in quality of life (MD 0.15, 95% CI -0.01 to 0.31). Biochemically, intravenous iron resulted in improved serum ferritin (MD 245.52μg/L, 95% CI 152.1 to 338.9) and haemoglobin levels (MD 4.65g/L, 95% CI 2.53 to 6.78). There was a higher risk of developing mild adverse events in the intravenous iron group compared with the placebo group (risk ratio 1.77, 95% CI 1.10 to 2.83); however, no differences were seen in serious adverse events (risk difference 0, 95% CI -0.01 to 0.01). The quality of evidence was rated 'low' and 'very low' for all outcome variables, except for fatigue, mainly due to most studies being judged as having a high risk of bias. In non-anaemic iron-deficient adults, the use of intravenous iron compared with placebo improved physical function and reduced fatigue scores. However, we remain uncertain about theefficacy in this population due to low-quality evidence, and there is a need for further studies to address potential impact on overall quality of life.

Two-year Effect of Semaglutide 2.4 mg Versus Placebo in Adults With Overweight or Obesity: STEP 5

The 2-year efficacy and safety of once-weekly (OW) subcutaneous semaglutide 2.4 mg versus placebo in adults with overweight/obesity was assessed in STEP 5 (NCT03693430). In STEP 5 (phase 3, double-blind, placebo-controlled trial), adults with body mass index (BMI) ≥30 kg/m2, or ≥27 kg/m2 with ≥1 weight-related comorbidity, without diabetes, were randomized 1:1 to 104 weeks’ treatment with OW semaglutide 2.4 mg or placebo. Co-primary endpoints were percent change in body weight (BW) and achievement of ≥5% weight loss.

POOLED SAFETY ANALYSIS OF LEBRIKIZUMAB IN PATIENTS WITH UNCONTROLLED ASTHMA FROM THREE RANDOMIZED CLINICAL TRIALS

<h3>Introduction</h3> LAVOLTA (L)I, LII, and ACOUSTICS were randomized, placebo-controlled, double-blinded, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting interleukin-13, in patients with uncontrolled asthma (LI, NCT01867125; LII, NCT01868061; ACOUSTICS, NCT01875003). These studies failed to provide consistently significant efficacy results in uncontrolled asthma.? Here, we report pooled safety analysis of lebrikizumab in patients during the 52-week placebo-controlled period from the three clinical trials. <h3>Methods</h3> Adults in LI, LII; adolescents (12–17 years) in ACOUSTICS, with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 second 40%–90% predicted, and stable background therapy were randomized 1:1:1 to lebrikizumab 125 mg or 37·5 mg or placebo (PBO) subcutaneously once every 4 weeks. Safety analyses were based on all patients who received at least one dose of study drug, with patients grouped by assigned treatment. Safety was assessed using summary of adverse events (AEs). <h3>Results</h3> The proportions of patients who experienced treatment-emergent AEs (combined lebrikizumab doses (LEB), 1281 [77%] of 1661 patients vs. PBO, 650 [78%] of 883 patients), serious AEs (7.6% vs. 8.5%), and AEs leading to study drug discontinuation (3.4% vs. 3.6%) were similar between LEB and PBO. One death occurred in the PBO group. Similar frequencies of key safety events, including conjunctivitis (LEB, 1.6%; PBO, 1.7%), infections and infestations (LEB, 51.6%; PBO, 50.7%), and eosinophil-related disorders (LEB, 0.2%; PBO, 0.2%) were noted; higher frequency of eosinophilia (>500 eosinophils/mm³) was reported (LEB, 1.1%; PBO, 0%). <h3>Conclusion</h3> The safety profile was similar between lebrikizumab and placebo in adults and adolescents with uncontrolled asthma.

Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses.

Evaluate the effects of once-weekly subcutaneous semaglutide 2.4 mg on cardiometabolic risk factors in people with overweight/obesity without diabetes in the STEP 1 and 4 trials. STEP 1 and 4 were phase III, 68-week, placebo-controlled trials of once-weekly semaglutide 2.4mg combined with lifestyle intervention; STEP 4 had a 20-week semaglutide run-in and 48-week randomized withdrawal period. Participants had a body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more weight-related comorbidity, without diabetes. Pre-specified endpoints were changes in waist circumference, systolic/diastolic blood pressure (SBP/DBP), lipids, fasting plasma glucose (FPG), fasting serum insulin and antihypertensive/lipid-lowering medication use. Post-hoc assessments included non-high-density lipoprotein (HDL) cholesterol, homeostatic model assessment of insulin resistance (HOMA-IR; STEP 1 only), atherosclerotic cardiovascular disease (ASCVD) risk (American College of Cardiology/American Heart Association algorithm; STEP 1 only) and cardiometabolic risk factors by weight loss achieved (<5%, 5% to <10%, 10% to <15%, or ≥15%) (STEP 1 only). Of the 1961 participants in STEP 1 and 803 in STEP 4, most had one or more complication/comorbidity at baseline, with dyslipidaemia and hypertension most prevalent. In STEP 1, reductions in waist circumference, SBP, DBP, FPG, fasting serum insulin, lipids and HOMA-IR were greater with semaglutide versus placebo (p ≤ .001). Reductions in SBP, non-HDL cholesterol, low-density lipoprotein cholesterol and FPG were generally greater with semaglutide than placebo within weight-loss categories. Non-significant ASCVD risk reductions were observed with semaglutide versus placebo (p > .05). In STEP 4, improvements in waist circumference, SBP, FPG, fasting serum insulin and lipids during the semaglutide run-in (week 0-20) were maintained over week 20-68 with continued semaglutide, but deteriorated following the switch to placebo (p < .001 [week 20-68]). Net reductions in antihypertensive/lipid-lowering medication use occurred with semaglutide versus placebo (both trials). Semaglutide may improve cardiometabolic risk factors and reduce antihypertensive/lipid-lowering medication use versus placebo in adults with overweight/obesity without diabetes. These potential benefits were not maintained after treatment discontinuation. STEP 1 NCT03548935, STEP 4 NCT03548987.

Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines.

Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines.