Double-blind Therapy Research Articles

Efficacy and safety of aniseed powder for treating gastrointestinal symptoms of COVID-19: a randomized, placebo-controlled trial.

Background: Gastrointestinal symptoms are prevalent amongst patients with a confirmed diagnosis of COVID-19 and may be associated with an increased risk of disease severity. This trial aimed to evaluate the efficacy and safety of aniseed (Pimpinella anisum L.) powder as an add-on therapy to standard care for treating gastrointestinal symptoms experienced by adults with an acute SARS-CoV-2 infection. Methods: The study was a randomized parallel-group double-blinded placebo-controlled add-on therapy trial. Adults with an acute SARS-CoV-2 infection who did not require hospitalization and reported at least one gastrointestinal symptom in the preceding 48h were assigned to either the aniseed or placebo group in a 1:4 ratio. All 225 participants (45 in the aniseed group and 180 in the placebo group) were instructed to use 25g of powdered aniseed or placebo twice daily for 2weeks. The primary outcomes were the proportion of patients who experienced an improvement of at least one point in the symptom score after adjusting for age group, gender, and time. Backwards stepwise logistic regression was applied to calculate the risk ratios. The clinical symptoms and adverse events were assessed at the beginning, 1week later, and at the end of the trial (week two). Results: Participants in the aniseed group were significantly more likely to report symptom improvement for abdominal pain [adjusted risk ratio (RR):0.55; 95% confidence interval (CI): 0.46-0.72], anorexia (RR:0.62; 95% CI: 0.47-0.82), and diarrhea (RR:0.19; 95% CI: 0.12-0.30), but not nausea/vomiting (RR:0.87; 95% CI: 0.71-1.08) or bloating (RR:0.87; 95% CI: 0.72-1.05). Two participants in the aniseed group and three participants in the placebo group reported mild to moderate adverse events. Conclusion: This study showed that 2weeks of aniseed powder containing trans-anethole (87%-94%) may help improve abdominal pain, anorexia, and diarrhea in COVID-19 patients. The findings align with the known biological, multitargeted activity of P. anisum and trans-anethole, which includes inhibiting SARS-CoV-2 along with other anti-infective, anti-inflammatory, antioxidant, hepatoprotective, and anti-dysbiosis properties. Multicenter trials with larger sample sizes and longer follow-up are warranted to confirm these findings. Clinical Trial Registration: Iranian Registry of Clinical Trials (IRCT20120506009651N3).

Efficacy and safety of upadacitinib maintenance therapy for moderately to severely active ulcerative colitis in patients responding to 8 week induction therapy (U-ACHIEVE Maintenance): overall results from the randomised, placebo-controlled, double-blind, phase 3 maintenance study

Upadacitinib is an oral, selective, and reversible JAK inhibitor with demonstrated efficacy in patients with moderately to severely active ulcerative colitis in a phase 2b induction trial, two phase 3 induction trials (U-ACHIEVE Induction and U-ACCOMPLISH), and a primary analysis of the first 451 patients entering a subsequent maintenance trial (U-ACHIEVE Maintenance). Here, we present overall results from the entire U-ACHIEVE Maintenance population. In this randomised, placebo-controlled, double-blind, phase 3 maintenance study done across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 251 clinical centres in 44 countries, patients aged 16-75 years with moderately to severely active ulcerative colitis (adapted Mayo score 5-9, centrally assessed endoscopic subscore of 2 or 3) for 90 days or more were randomly assigned (2:1) to double-blind upadacitinib 45 mg once daily or placebo induction therapy in the phase 2b induction trial or two phase 3 induction trials. Patients with a clinical response per adapted Mayo score after 8 weeks were randomly reassigned (1:1:1) using web-based interactive response technology to 52 week double-blind maintenance therapy with placebo, upadacitinib 15 mg, or upadacitinib 30 mg once daily. Efficacy was analysed at week 52 in the intention-to-treat population, which included all patients randomly reassigned who received at least one dose of study drug. The primary endpoint was clinical remission per adapted Mayo score. Safety through week 52 was assessed with exposure-adjusted event rates (EAERs; events per 100 patient-years) in upadacitinib 45 mg once daily 8-week induction responders who were enrolled per protocol for 44-week or 52-week maintenance therapy (ie, the intention-to-treat population plus patients who received up to 44 weeks' maintenance therapy under earlier protocol amendments) and received at least one dose of study drug. The study is registered with ClinicalTrials.gov, NCT02819635 and is complete. Between Sept 3, 2016, and Jan 14, 2021 987 patients received the upadacitinib 45 mg once daily induction therapy in the phase 2b trial, U-ACHIEVE Induction, or U-ACCOMPLISH. 681 patients with a clinical response to the induction therapy (319 from U-ACHIEVE Induction, 341 from U-ACCOMPLISH, and 21 from the phase 2b induction trial) received placebo (n=223), upadacitinib 15 mg once daily (n=225), or upadacitinib 30 mg once daily (n=233) in U-ACHIEVE Maintenance and were included in this analysis. A greater proportion of patients achieved the primary endpoint with upadacitinib 15 mg (40·4%) and 30 mg once daily (53·6%) versus placebo (10·8%; both p<0·0001 vs placebo). For safety, 746 patients were analysed, representing 552·9 patient-years of exposure; the most common grade 3-4 treatment-emergent adverse events were worsening of ulcerative colitis in nine (4%) patients with placebo, and COVID-19 pneumonia and cryptococcal pneumonia in two (1%) patients each with upadacitinib 30 mg once daily. Higher EAERs of the following treatment-emergent events of special interest were observed with upadacitinib versus placebo: herpes zoster (6·0 events per 100 patient-years with upadacitinib 15 mg once daily and 7·3 events per 100 patient-years with upadacitinib 30 mg once daily vs none per 100 patient-years with placebo [12 and 16 vs no events, respectively), hepatic disorders (17·0 and 9·2 vs 5·9 events per 100 patient-years [34 and 20 vs eight events, respectively), creatine phosphokinase elevation (8·0 and 10·1 vs 3·7 events per 100 patient-years [16 and 22 vs five events], respectively), and neutropenia (5·5 and 8·7 vs 5·2 events per 100 patient-years [11 and 19 vs seven events], respectively). One (<1% of patients) adjudicated major adverse cardiovascular event occurred with placebo and one (<1% of patients) with upadacitinib 30 mg once daily (EAERs 0·7 and 0·5 events per 100 patient-years, respectively). Two (1% of patients) venous thromboembolic events occurred with upadacitinib 15 mg once daily and two (1% of patients) with upadacitinib 30 mg once daily (EAERs 1·0 and 0·9 events per 100 patient-years, respectively). All adjudicated major adverse cardiovascular events and venous thromboembolic events with upadacitinib occurred in patients with relevant known risk factors. Consistent with the primary analysis done among a smaller population, both maintenance doses of upadacitinib showed a positive benefit-risk profile in patients with moderately to severely active ulcerative colitis. Upadacitinib represents an effective treatment option for this population, for whom a large unmet need persists. AbbVie.

Improvement in Depression Symptoms Measured by Montgomery-Åsberg Depression Rating Scale and Quick Inventory of Depressive Symptomatology-Self Rated Items after Randomised Double-blind COMP360 Psilocybin Therapy for Treatment-resistant Depression

IntroductionCOMP360 is a synthetic, proprietary, purified form of psilocybin in development for treatment-resistant depression (TRD) with FDA Breakthrough Therapy designation. In a recent phase IIb study, COMP360 psilocybin 25mg was superior to 1mg on change from baseline (CFB) to Week 3 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score (primary efficacy endpoint), when administered alongside psychological support. Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR 16) total score (exploratory efficacy endpoint) showed similar results.ObjectivesTo analyse changes in specific depression symptoms after psilocybin treatment in the aforementioned study, as measured by individual item scores on the MADRS and QIDS-SR 16 (range 0-6 and 0-3).MethodsParticipants with TRD were randomised to single doses of psilocybin 25mg (n=79), 10mg (n=75), or 1mg (n=79). A remote, blinded rater assessed the MADRS at Baseline, Day 2 (the day post-psilocybin), and Weeks 1, 3, 6, 9, and 12. The QIDS-SR 16 was self-rated at Baseline, Day 1, Day 2, and Weeks 1, 2, 3, 6, 9, and 12. At each time point, descriptive statistics were calculated for each MADRS and QIDS-SR 16 individual item score.ResultsAt Week 3, MADRS items with the largest differences in mean CFB in the 25mg arm were Inability to Feel, Apparent Sadness, Lassitude, and Reported Sadness. Greater improvement in the 25mg arm was apparent from Day 2 and remained to Week 12 (Lassitude remained to Week 6 only). On the QIDS-SR 16, the item with the largest difference in mean CFB at Week 3 in the 25mg arm was in Feeling Sad and remained evident to Week 12 (Table 1).Table 1.Item (mean CFB at Week 3 [standard deviation])Psilocybin 25mgPsilocybin 10mgPsilocybin 1mgMADRS - Inability to Feel-1.8 [1.81]-0.9 [1.54]-0.8 [1.61]MADRS - Apparent Sadness-1.7 [1.94]-1.1 [1.60]-0.9 [1.62]MADRS - Lassitude-1.6 [1.81]-1.2 [1.83]-0.8 [1.58]MADRS - Reported Sadness-1.6 [1.95]-1.0 [1.52]-0.6 [1.53]QIDS-SR16- Feeling Sad-1.1 [1.08]-0.8 [1.07]-0.4 [0.91]ConclusionsA single administration of COMP360 psilocybin therapy rapidly and dose-relatedly improved symptoms of depressed mood and anhedonia – the two key symptoms of depression. As anhedonia is predictive of poorer treatment response, and improvements in anhedonia correlate with improvements in functioning, it is important to understand the impact of treatments on this symptom.Disclosure of InterestG. Goodwin Shareolder of: COMPASS Pathways, P1Vital, and P1Vital products , Employee of: COMPASS Pathways, L. Marwood Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, S. Mistry Employee of: COMPASS Pathways, A. Nowakowska Employee of: COMPASS Pathways, H. Simmons Employee of: COMPASS Pathways, J. Tsai Employee of: COMPASS Pathways, S. Williams Employee of: COMPASS Pathways, M. Young Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, E. Malievskaia Employee of: COMPASS Pathways

Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial

Background & aimsNovel, effective treatments for Helicobacter pylori infection are needed. This study evaluated the efficacy of vonoprazan, a potassium-competitive acid blocker, vs standard treatment on H pylori eradication in the United States and Europe. MethodsIn a randomized, controlled, phase 3 trial, treatment-naïve adults with H pylori infection were randomized 1:1:1 to open-label vonoprazan dual therapy (20 mg vonoprazan twice daily; 1 g amoxicillin 3 times daily), or double-blind triple therapy twice a day (vonoprazan 20 mg or lansoprazole 30 mg; amoxicillin 1 g; clarithromycin 500 mg) for 14 days. The primary outcome was noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains (noninferiority margin = 10%). Secondary outcomes assessed superiority in eradication rates in clarithromycin-resistant infections, and in all patients. ResultsA total of 1046 patients were randomized. Primary outcome eradication rates (nonresistant strains): vonoprazan triple therapy 84.7%, dual therapy 78.5%, vs lansoprazole triple therapy 78.8% (both noninferior; difference 5.9%; 95% confidence interval [CI], −0.8 to 12.6; P < .001; difference –0.3%; 95% CI, −7.4 to 6.8; P = .007, respectively). Eradication rates in clarithromycin-resistant infections: vonoprazan triple therapy 65.8%, dual therapy 69.6%, vs lansoprazole triple therapy 31.9% (both superior; difference 33.9%; 95% CI, 17.7–48.1; P < .001; difference 37.7%; 95% CI, 20.5–52.6; P < .001, respectively). In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5%, difference 12.3%; 95% CI, 5.7–18.8; P < .001; difference 8.7%; 95% CI, 1.9–15.4; P = .013). Overall frequency of treatment-emergent adverse events was similar between vonoprazan and lansoprazole regimens (P > .05). ConclusionBoth vonoprazan-based regimens were superior to proton pump inhibitor–based triple therapy in clarithromycin-resistant strains and in the overall study population. ClinicalTrials.gov; NCT04167670.

A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of immunosuppression in biopsy-proven virus-negative myocarditis or inflammatory cardiomyopathy (IMPROVE-MC).

Myocarditis is frequently associated with poor prognosis as there is no evidence-based treatment. Therefore, current international recommendations indicate that a well-designed prospective trial to confirm benefits from immunosuppressive therapy is highly warranted. The aim of the IMPROVE-MC study is to assess the efficacy and safety of immunosuppressive treatment compared with placebo on top of the guideline-recommended medical therapy in patients with biopsy-proven virus-negative myocarditis/inflammatory cardiomyopathy. The IMPROVE-MC (ClinicalTrials.gov: NCT04654988) is a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial that will recruit 100 adults, with biopsy-proven myocarditis/inflammatory cardiomyopathy, with left ventricular ejection fraction (LVEF) ≤ 45% and ≥ 3-month history of symptoms. Patients will be randomized (1:1 ratio) to a group treated with prednisone and azathioprine vs. placebo. Patients will undergo 1-year double-blind therapy followed by a 1-year observation period to assess the long-term effects of the treatment. Apart from a routine clinical work-up, all patients will undergo cardiac magnetic resonance (CMR) and biopsy during screening and 1 year after applying the therapy. Primary endpoint is a change from baseline in LVEF at 12 months. Secondary endpoints are related to clinical evaluation (including New York Heart Association class, distance in 6-minute walk test, number of patients with the need for hospitalization), laboratory findings (biomarkers of fibrosis and myocardial necrosis, concentration of anti-heart auto-antibodies, heart tissue immunohistologic assessment), diagnostic tools (e.g., changes of echocardiographic, CMR and Holter-ECG parameters) and quality of life. The IMPROVE-MC study will provide high-quality scientific data on the efficacy and safety of immunosuppressive therapy for patients with biopsy-proven myocarditis. Trial registration number and date of registration: ClinicalTrials.gov:NCT04654988; 04/12/2020.

Long-term therapeutic effect of eslicarbazepine acetate in children: An open-label extension of a cognition study in children aged 6–16 years

ObjectiveIn Europe, eslicarbazepine acetate (ESL) is approved as adjunctive therapy for the treatment of focal seizures (FS) in children aged >6 years. In the US, ESL is approved as both monotherapy and adjunctive therapy for the treatment of FS in patients aged ≥4 years. In a phase II study of children aged 6–16 years with FS, ESL had no significant effects on attention or behavioral functioning and decreased seizure frequency during double-blind therapy and a 1-year open-label extension (OLE). This report presents data from an additional 2-year OLE of the phase II study. MethodsPrevious recipients of ESL or placebo were treated with open-label ESL (10–30 mg/kg/day, adjusted for clinical response and/or adverse events [AEs]). Safety was assessed by incidence of treatment-emergent AEs (TEAEs). Efficacy endpoints were treatment retention time and change from baseline in Clinical Global Impression-Severity (CGI-S) scale scores. ResultsForty-two patients entered and 31 (73.8%) completed the 2-year OLE. Median treatment retention time was 735 (95% confidence interval 728–741) days. Seven patients (17% of total, 23% of completed) experienced ≥1 TEAE during the 2-year OLE, mostly of mild or moderate intensity. The incidence of serious TEAEs was low (n = 2; 5% of total, 6% of completed) and none were related to ESL. One child was withdrawn because of splenomegaly that was considered possibly related to ESL. The only change from baseline in CGI-S was a 0.5-point reduction in the severity of illness score. All findings were consistent across patient subgroups based on previous double-blind treatment (placebo or ESL) and patient age (6–11 or 12–16 years). ConclusionsThe majority of patients remained on ESL during the 2-year OLE, and treatment efficacy was maintained. Adverse events were consistent with the known safety profile of ESL, and no new safety signals were identified.

Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML

BackgroundOverall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial.Methods/DesignThis is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%.Ethics and disseminationEthical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.Trial statusProtocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st.Trial registrationClinicalTrials.govNCT04093505; EudraCT 2019-003913-32. Registered on October 30, 2018.

Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure.

Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure.

Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction

Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. Methods: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. Results: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67–0.87; P &lt;0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50–0.90; P =0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47–0.87; P =0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56–0.78; P &lt;0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63–0.78; P &lt;0.0001). Conclusions: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057977.

OP0249 LONG-TERM EXTENSION RESULTS OF RISE-SSC, A RANDOMIZED TRIAL OF RIOCIGUAT IN PATIENTS WITH EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (DCSSC)

OP0249 LONG-TERM EXTENSION RESULTS OF RISE-SSC, A RANDOMIZED TRIAL OF RIOCIGUAT IN PATIENTS WITH EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (DCSSC)

350 Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis in Adolescents and Adults: Results From a Phase 3, Randomized, Placebo-Controlled Trial

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. METHODS: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed. RESULTS: A total of 322 patients were randomized (BOS, n = 215; placebo, n = 107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n = 213; placebo, n = 105) (Table 1). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, P &lt; 0.001; 52.6% vs 39.1%, P = 0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n = 197) than the placebo group (n = 89) (−13.0 vs −9.1; P = 0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n = 202) than placebo (n = 93) (−4.0 vs −2.2; P &lt; 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo. No life-threatening TEAEs were reported. CONCLUSION: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria

Background: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. Objective: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H₁-antihistamines. Methods: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D₂ (PGD₂)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. Results: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD₂-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. Conclusions: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD₂-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD₂/CRTh2 pathway will be an ­effective treatment for CSU.

Role of thiamine supplementation in the treatment of patients with heart failure: A double-blind randomized controlled trial

Introduction: The role of thiamine supplementation in heart failure (HF) patients has shown conflicting results and has not been adequately studied. Aims and Objectives: The aim and objective were to determine whether thiamine supplementation will provide clinical, biochemical, and echocardiographic benefit in congestive HF patients. Materials and Methods: In this single-center, double-blind, prospective randomized controlled trial, HF patients with varied etiology were included. Patients were randomly allocated to 1 week of inpatient double-blind intravenous therapy with either placebo or thiamine. Parameters studied included clinical, Echo left ventricular ejection fraction (LVEF), and thiamine pyrophosphate effect (TPPE) levels before/after treatment. After completion of 1-week treatment, all patients were given oral thiamine and evaluated at the outpatient clinic after 6 weeks. Results: A total of fifty patients were studied. There was no difference at baseline in mean age (61.4 ± 7.1 vs. 62.4 ± 8.0 years), sex (males 52% vs. 56%), etiology (idiopathic dilated cardiomyopathy 68% vs. 60%, ischemic heart disease 20% vs. 24%), clinical parameters, TPPE levels (16.4 ± 5.2 vs. 16.2 ± 6.5%), and LVEF (28.1% ± 6.7% vs. 28.3% ± 6.6%) in thiamine as compared to placebo group. After 1 week of treatment, there was significant improvement in systolic blood pressure (119.2 ± 18.3 vs. 106.1 ± 18.9 mmHgP Conclusions: Thiamine supplementation significantly improved clinical and echocardiographic parameters. Thiamine supplementation is cost-effective, is benign, and is easily available with significant clinical benefits.

DURATION-8 Randomized Controlled Trial 104-Week Results—Once-Weekly Exenatide (ExQW) plus Once-Daily Dapagliflozin (DAPA) vs. ExQW or DAPA Alone

In patients with T2D uncontrolled on metformin alone, ExQW + DAPA significantly reduced glycemia, body weight and systolic blood pressure compared to ExQW + placebo (PBO) or DAPA + PBO at 28 weeks (NCT02229396). Here, we examined efficacy and safety after 104 weeks of double-blind therapy. Of 695 patients randomized, 431 (62%) completed 104 weeks; 4.3% withdrew due to adverse events (AEs). Absolute reductions and between-group differences in A1C were maintained over 104 weeks (Figure). Clinically relevant changes vs. baseline in other efficacy end points were also observed (Table). AEs and serious AEs were balanced across treatment groups. Hypoglycemia incidence was low (Table). In conclusion, ExQW + DAPA maintained efficacy over 104 weeks with no unexpected safety concerns.Changes in efficacy end points and hypoglycemia incidence from baseline through week 104ExQW+DAPA N=228 n=147ExQW+PBO N=227 n=132DAPA+PBO N=230 n=152ExQW+DAPA vs ExQW+PBOExQW+DAPA vs DAPA+PBOA1C, % BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 9.29 (1.06) −1.98 (0.09) −1.75 (0.10) −1.70 (0.11)□ 9.26 (1.08) −1.60 (0.10) −1.38 (0.10) −1.29 (0.12)□ 9.25 (1.02) −1.39 (0.09) −1.23 (0.10) −1.06 (0.12)□ □ −0.38 (0.13)** −0.37 (0.14)** −0.42 (0.15)**□ □ −0.59 (0.13)*** −0.52 (0.13)*** −0.64 (0.15)***FPG, mg/dL BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 195.0 (53.5) −65.8 (2.9) −63.0 (2.9) −49.0 (4.1)□ 189.3 (49.8) −45.8 (3.0) −45.4 (3.1) −29.8 (4.5)□ 188.5 (44.2) −49.2 (2.9) −39.8 (3.0) −21.9 (4.6)□ □ −20.1 (4.0)*** −17.6 (4.1)*** −19.2 (5.9)***□ □ −16.6 (3.9)*** −23.3 (4.0)*** −27.1 (6.0)***2h-PPG, mg/dL BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 268.5 (67.5) −87.8 (4.1) −82.4 (4.8) −86.2 (5.9)□ 266.1 (67.2) −60.1 (4.3) −64.0 (5.1) −79.0 (7.0)□ 261.5 (60.2) −61.1 (4.1) −59.6 (5.0) −64.0 (6.6)□ □ −27.7 (5.2)*** −18.4 (6.3)** −7.2 (7.9)□ □ −26.8 (5.1)*** −22.8 (6.2)*** −22.2 (7.9)**Body weight, kg BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 92.1 (21.8) −3.6 (0.3) −3.3 (0.4) −2.5 (0.4)□ 89.1 (18.7) −1.6 (0.3) −1.5 (0.4) −0.8 (0.5)□ 90.9 (19.6) −2.2 (0.3) −2.3 (0.4) −3.0 (0.5)□ □ −2.0 (0.4)*** −1.8 (0.5)*** −1.7 (0.6)**□ □ −1.3 (0.4)*** −1.0 (0.5) +0.5 (0.6)Systolic BP, mmHg BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 130.7 (12.1) −4.3 (0.8) −4.5 (0.8) −3.1 (1.0)□ 129.3 (12.5) −1.2 (0.8) −0.7 (0.9) −0.1 (1.1)□ 129.6 (12.8) −1.8 (0.8) −2.7 (0.8) −1.1 (1.0)□ □ −3.0 (1.1)** −3.9 (1.1)*** −3.0 (1.4)*□ □ −2.4 (1.1)* −1.8 (1.1) −2.0 (1.4)Hypoglycemia† through 104 wks Major, % pts Minor, % pts Other, % ptsN=231 0 1.7 6.9N=230 0 0 3.5N=233 0 0.4 3.4*P&amp;lt;0.05, **P&amp;lt;0.01, ***P≤0.001 (P-values at wk 52 and wk 104 are nominal). BL, baseline, BP, blood pressure; FPG, fasting plasma glucose; LSM, least-squares mean; N, number comprising the intention-to-treat analysis set; n, number completing 104 weeks of treatment; 2h-PPG, 2-hour post-prandial glucose; pts, patients; SD, standard deviation; SE, standard error; wk, week. †Major hypoglycemia: loss of consciousness, seizure or coma resolving after glucagon or glucose administration or events requiring third-party assistance due to severe impairment of consciousness or behavior with blood glucose concentration &amp;lt;54 mg/dL. Minor hypoglycemia: non-major event with symptoms consistent with hypoglycemia and blood glucose concentration &amp;lt;54 mg/dL. Other hypoglycemia: events not meeting major or minor hypoglycemia criteria. Disclosure S. Jabbour: None. C. Guja: Consultant; Self; AstraZeneca, Bayer AG, Eli Lilly and Company, Merck KGaA, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Boehringer Ingelheim GmbH. E. Hardy: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S. Bhattacharya: None. P.K. Ohman: Employee; Self; AstraZeneca. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson &amp; Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc..

Safety and Efficacy of Budesonide Oral Suspension Maintenance Therapy in Patients With Eosinophilic Esophagitis

We aimed to determine the safety and efficacy of budesonide oral suspension (BOS) maintenancetherapy in patients with eosinophilic esophagitis (EoE). We performed an open-label extension study of a 12-week, multicenter, randomized, double-blind, placebo-controlled trial. Patients with EoE (11-40 years old) who completed double-blind BOS (n = 45) or placebo therapy (n = 37) received 24 weeks' open-label BOS (2.0mg once daily for 12 weeks, with optional dose increase [1.5-2.0 mg twice daily] for 12 weeks thereafter). Predefined efficacy outcomes included: proportion of patients with a histologic response (≤6 eosinophils/high-power field [eos/hpf]) and change in mean peak eosinophil counts after 24 weeks. Analyses were stratified by patients who received placebo (placebo/BOS) or BOS (BOS/BOS) during the double-blind trial. BOS was well tolerated and drug-related adverse events were uncommon (placebo/BOS, 19% [7/37]; BOS/BOS, 4% [2/45]). Incidence of oral candidiasis (1 per group) and esophageal candidiasis (placebo/BOS group, n = 4) remained low. Changes in morning serum cortisol levels were not clinically relevant. A histologic response was observed in 49% (16/33) of patients receiving placebo/BOS and 23% (9/39) receiving BOS/BOS. Mean peak eosinophil counts (baseline vs week 24 or early termination) were: placebo/BOS, 118.8 vs 29.1; P < .001 and BOS/BOS, 38.1 vs 72.4; P = .01. Of the patients who responded to double-blind therapy, 42% maintained a histologic response during the open-label extension; 4% of nonresponders gained response. In an open-label extension study of patients with EoE, BOS was well tolerated and drug-related adverse events were uncommon. BOS maintained a histologic response in some initial responders, but few initial nonresponders had a response. ClinicalTrials.gov no: NCT01642212.

Efficacy and safety of twice-daily rabeprazole maintenance therapy for patients with reflux esophagitis refractory to standard once-daily proton pump inhibitor: the Japan-based EXTEND study

BackgroundRabeprazole at 10 or 20 mg twice daily (b.i.d.) has been reported to be highly effective in the treatment of proton pump inhibitor (PPI)-resistant reflux esophagitis (RE) that is refractory to the standard once-daily PPI regimen. We evaluated the efficacy and safety of rabeprazole maintenance therapy at 10 mg once daily (q.d.) or b.i.d. for longer than 8 weeks.MethodsPatients with RE refractory to standard PPI regimens for at least 8 weeks were enrolled. They were treated with rabeprazole at 10 or 20 mg b.i.d. for 8 weeks during the open-label treatment period. After endoscopic examination, those with confirmed healing entered the subsequent double-blind maintenance therapy. During this period, the subjects were randomized to receive rabeprazole 10 mg q.d. (control) or 10 mg b.i.d. The primary endpoint was the endoscopic no-recurrence rate at Week 52.ResultsIn total, 517 subjects entered the treatment, and 359 subjects continued on maintenance therapy. The full analysis set for central assessment included 343 subjects. The no-recurrence rate at Week 52 was significantly higher in the b.i.d. group (73.9%; p < 0.001, χ2 test) than in the q.d. group (44.8%). In particular, the b.i.d. regimen was more effective in all subgroups with Los Angeles Classification Grade B to D at treatment entry.ConclusionsIn the maintenance treatment of PPI-resistant RE, rabeprazole at 10 mg b.i.d. exerted a stronger recurrence-preventing effect than 10 mg q.d. over 52 weeks. No particular safety issues were noted during long-term administration.ClinicalTrials.gov number: NCT02135107.

Effects on α- and β-cell function of sequentially adding empagliflozin and linagliptin to therapy in people with type 2 diabetes previously receiving metformin: An exploratory mechanistic study.

To investigate the effect of sequential treatment escalation with empagliflozin and linagliptin on laboratory markers of α- and β-cell function in people with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy. A total of 44 people with T2DM received 25 mg empagliflozin for a duration of 1 month in an open-label fashion (treatment period 1 [TP1]). Thereafter, they were randomized to a double-blind add-on therapy with linagliptin 5 mg or placebo (treatment period 2 [TP2]) for 1 additional month. α- and β-cell function was assessed using a standardized liquid meal test and an intravenous (i.v.) glucose challenge. Efficacy measures comprised the areas under the curve for glucose, insulin, proinsulin and glucagon after the liquid meal test and the assessment of fast and late-phase insulin release after an i.v. glucose load with a subsequent hyperglycaemic clamp. Empagliflozin reduced fasting and postprandial plasma glucose levels, associated with a significant reduction in postprandial insulin levels and an improvement in the conversion rate of proinsulin (TP1). The addition of linagliptin during TP2 further improved postprandial glucose levels, probably as a result of a marked reduction in postprandial glucagon concentrations (TP2). The insulin response to an i.v. glucose load increased during treatment with empagliflozin (TP1), and further improved after the addition of linagliptin (TP2). After metformin failure, sequential treatment escalation with empagliflozin and linagliptin is an attractive treatment option because of the additive effects on postprandial glucose control, probably mediated by complementary effects on α- and β-cell function.

Urine Fibrosis Markers and Risk of Allograft Failure in Kidney Transplant Recipients: A Case-Cohort Ancillary Study of the FAVORIT Trial

Kidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown. Case-cohort study. The FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257). Using spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine α1-microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide). Death-censored allograft failure. In models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure. We lack kidney biopsy data, BK titers, and HLA antibody status. Urine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR.

Efficacy of prednisone for the treatment of ocular myasthenia (EPITOME): A randomized, controlled trial.

In this study we evaluated the safety, tolerability, and efficacy of prednisone in patients with ocular myasthenia gravis (OMG) concurrently treated with pyridostigmine. This investigation was a randomized, double-blind, placebo-controlled trial. Participants whose symptoms failed to remit on pyridostigmine were randomized to receive placebo or prednisone, initiated at 10 mg every other day, and titrated to a maximum of 40 mg/day over 16 weeks. The primary outcome measure was treatment failure. Fewer subjects were randomized than the 88 planned. Of the 11 randomized, 9 completed 16 weeks of double-blind therapy. Treatment failure incidence was 100% (95% CI 48%-100%) in the placebo group (n = 5) vs. 17% (95% CI 0%-64%) in the prednisone group, P = 0.02 (n = 6). Median time to sustained minimal manifestation status (MMS) was 14 weeks, requiring an average prednisone dose of 15 mg/day. Adverse events were infrequent and generally mild in both groups. A strategy of low-dose prednisone with gradual escalation appears to be safe, well-tolerated, and effective in treating OMG.

Effect of high-dose atorvastatin on the cardiovascular risk associated with individual components of metabolic syndrome: a subanalysis of the Treating to New Targets (TNT) study.

To investigate the impact of intensive lipid-lowering with high-dose atorvastatin on the cardiovascular risk associated with individual metabolic syndrome components [high body mass index (BMI), elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, hypertension and elevated fasting glucose] in patients with coronary heart disease (CHD). Patients with clinically evident, stable CHD and low-density lipoprotein (LDL) cholesterol <3.4 mmol/l (130 mg/dl) were randomized to double-blind therapy with atorvastatin 10 mg/day (n = 5006) or 80 mg/day (n = 4995) after an 8-week open-label run-in with atorvastatin 10 mg. The median follow-up was 4.9 years. The impact of individual metabolic syndrome risk factors was tested on the primary endpoint, which was the occurrence of a first major cardiovascular event. On-treatment LDL cholesterol was 2.6 mmol/l (101 mg/dl) with atorvastatin 10 mg and 2.0 mmol/l (77 mg/dl) with atorvastatin 80 mg. Among patients receiving atorvastatin 10 mg, the presence of each individual metabolic syndrome component significantly increased the risk of major cardiovascular events compared with the absence of each (BMI, p = 0.014; triglycerides, p = 0.006; HDL cholesterol, p = 0.0006; hypertension, p < 0.0001; and fasting glucose p < 0.0001). In patients receiving atorvastatin 80 mg, elevated triglycerides and fasting glucose were no longer significant predictors of major cardiovascular events. The predictive power of hypertension on the risk of major cardiovascular events was reduced in patients treated with atorvastatin 80 mg, although it remained a significant predictor. Treatment with high-dose atorvastatin to a mean LDL cholesterol level of 2.0 mmol/l (77 mg/dl) considerably attenuated the predictive power associated with three metabolic syndrome components.