scholarly journals Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD

2021 ◽  
pp. 135245852198892
Author(s):  
Bruce AC Cree ◽  
Jeffrey L Bennett ◽  
Ho Jin Kim ◽  
Brian G Weinshenker ◽  
Sean J Pittock ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Evaluation Method ◽  
Demographic Groups ◽  
Patient Demographics ◽  
Treatment History ◽  
Previous Therapy ◽  
Hazard Ratios ◽  
Secondary Endpoints ◽  
Post Hoc ◽  
Attack Type

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo. Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses. Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints. Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends. Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy. The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Estimated treatment effect of ticagrelor versus aspirin by investigator-assessed events compared with judgement by an independent event adjudication committee in the SOCRATES trial

2019 ◽  
Vol 14 (9) ◽  
pp. 908-914 ◽  
Author(s):  
J Donald Easton ◽  
Hans Denison ◽  
Scott R Evans ◽  
Mikael Knutsson ◽  
Pierre Amarenco ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Treatment Effect ◽  
Standard Procedure ◽  
Clinical Event ◽  
Minor Stroke ◽  
Double Blind ◽  
Hazard Ratios ◽  
Ischemic Attack ◽  
Post Hoc ◽  
Adjudication Committee

Background Adjudication of endpoints is a standard procedure in cardiovascular clinical trials. However, several studies indicate that the benefit of adjudication in estimating treatment effect may be limited. Aims This post hoc analysis of SOCRATES (NCT01994720) compared the treatment effects and investigated the agreement of clinical event assessment by site investigators and independent adjudicators. Methods SOCRATES compared ticagrelor and aspirin in 13,199 patients with acute minor stroke or high-risk transient ischemic attack. The primary endpoint was stroke, myocardial infarction, or death. Stroke was the major component of the primary endpoint and a secondary endpoint. The endpoints were adjudicated by a blinded independent committee. We compared the treatment effect on the primary endpoint and stroke alone based on the investigators' and adjudicators' assessments, and investigated the agreement rate on the stroke endpoint and major hemorrhages. Results The hazard ratios (95% confidence interval) for ticagrelor versus aspirin therapy for the primary endpoint were 0.89 (0.78–1.01) when calculated on adjudicator-assessed events and 0.88 (0.78–1.00) for investigator-assessed events. The hazard ratios (95% confidence intervals) for stroke were 0.86 (0.75–0.99) based on the adjudicators' diagnoses and 0.85 (0.75–0.97) based on the investigators' diagnoses. The overall agreement between adjudicator- and investigator-diagnosed stroke was 91%, and for major hemorrhages was 88%. Conclusions In SOCRATES, there was no clinically meaningful difference in the estimated treatment effect, on either the primary endpoint or stroke, by using investigator- or adjudicator-assessed events. Double-blind treatment outcome studies with stroke endpoints may not benefit from adjudication. Trial Registration ClinicalTrials.gov Identifier: NCT01994720.

scholarly journals Erythropoietic Protoporphyria: Phase 2 Clinical Trial Results Evaluating the Safety and Effectiveness of Dersimelagon (MT-7117), an Oral MC1R Agonist

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 51-51
Author(s):  
Manisha Balwani ◽  
Herbert L. Bonkovsky ◽  
Kirstine J Belongie ◽  
Karl E Anderson ◽  
Fumihiro Takahashi ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Sun Exposure ◽  
Sunlight Exposure ◽  
Prodromal Symptom ◽  
Tolerability Profile ◽  
Phase 2 ◽  
Prodromal Symptoms ◽  
Secondary Endpoints ◽  
Post Hoc ◽  
Daily Time

Introduction Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) are inborn errors of heme biosynthesis caused by the abnormal accumulation of erythrocyte protoporphyrin IX (ePPIX). These protoporphyrias are characterized by excruciating painful attacks on prolonged sunlight exposure. Before the onset of phototoxic pain, patients experience characteristic prodromal symptoms which serves as a warning signal to avoid further sun exposure. Of note, patients with higher ePPIX levels report shorter times to symptoms compared to patients with lower median ePPIX levels (JAMA Derm, 2017; 153). Here we report the safety and effectiveness of Dersimelagon (MT-7117), a novel, orally-administered, small molecule, selective melanocortin-1 receptor (MC1R) agonist that increases skin melanin without sun exposure and is being developed to increase light tolerance in EPP/XLP patients. Results of the primary, secondary efficacy endpoints, and post-hoc subgroup analyses evaluating effects of baseline ePPIX levels on treatment response will be presented. Methods The MT-7117-A01 (ENDEAVOR) study was a Phase 2, multi-center, randomized, placebo-controlled study with a 16-week double-blind treatment period. A total of 102 EPP/XLP patients were randomized to 3 groups: placebo once daily (QD) (n=35 [31 EPP/4 XLP]), MT-7117 100 mg QD (n=33 [31 EPP/2 XLP]), and MT-7117 300 mg QD (n=34 [31 EPP/3 XLP]). Results of the primary endpoint, increase in the average daily time (min) to first prodromal symptom during sunlight exposure, and secondary endpoints including 1) average daily duration of sunlight exposure without prodromal symptoms, 2) total number of sunlight exposure episodes with prodromal symptoms, and 3) total number of pain events, and post-hoc subgroup analyses evaluating baseline median ePPIX levels are presented here. Safety and tolerability were also assessed. Results There was a significant improvement in average daily time (&gt;50 min) to first prodromal symptom [the primary endpoint] associated with sunlight exposure in subjects treated with MT-7117 100 mg (p=0.008) or 300 mg (p=0.003) compared to placebo at Week 16. Multiple secondary endpoints supported primary endpoint. There was a significant increase in average daily minutes of sunlight exposure without prodromal symptoms at Week 16 in 100 mg (p=0.009) and 300 mg (p=0.004) treated subjects compared to placebo, with an increased average exposure time without prodromal symptoms of ~50 min in MT-7117 subjects at both doses compared to placebo. There was also a 40% reduction in the total number of sunlight exposure episodes with prodromal symptoms in 100 mg (p=0.019) and 300 mg (p=0.006) subjects compared to placebo. There was a significant decrease in the total number of pain events reported in 100 mg (p=0.027, 60% reduction) and 300 mg (p=0.028, 50% reduction) subjects compared to placebo. The post-hoc subgroup analysis evaluating the effects of baseline ePPIX levels in subjects grouped based on the baseline median ePPIX level of 1981 µg/dL. There was a statistically significant increase in average daily time to first prodromal symptom in the subgroup with ePPIX levels ≥1981 µg/dL receiving 100 mg (p=0.020) and 300 mg (p=0.003) compared to placebo. A trend to beneficial effect was also observed for the subgroup of subjects with ePPIX levels &lt;1981 µg/dL receiving 100 mg (p=0.180) and 300 mg (p=0.216) compared to placebo. MT-7117 had an acceptable safety and tolerability profile. The most common treatment-related treatment emergent adverse reactions were nausea (27.9%), ephelides (23.5%), and skin hyperpigmentation (20.6%). Conclusion The results of the primary efficacy endpoint and multiple secondary endpoints in this Phase 2 study indicate that the oral, MC1R agonist dersimelagon was efficacious after 16 weeks of treatment in increasing symptom-free light exposure in patients with EPP or XLP at doses of 100 and 300 mg QD and showed an acceptable safety and tolerability profile. The post-hoc analyses showed more profound and statistically significant efficacy at both doses for the subgroup with higher baseline median ePPIX levels. Disclosures Balwani: Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding; Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording. Anderson:Alnylam Pahrmaceuticals: Consultancy; Recordati Rare Diseases: Consultancy; Mitsubishi Tanabe Pharma: Consultancy.

scholarly journals Randomised, controlled trial of erenumab for the prevention of episodic migraine in patients from Asia, the Middle East, and Latin America: The EMPOwER study

Cephalalgia ◽  
2021 ◽  
pp. 033310242110241
Author(s):  
Shuu-Jiun Wang ◽  
Artemio A Roxas ◽  
Bibiana Saravia ◽  
Byung-Kun Kim ◽  
Debashish Chowdhury ◽  
...  
Keyword(s):  
Latin America ◽  
Middle East ◽  
Primary Endpoint ◽  
Episodic Migraine ◽  
Acute Migraine ◽  
Efficacy And Safety ◽  
Medication Treatment ◽  
Significant Difference ◽  
Specific Medication ◽  
Secondary Endpoints

Objective EMPOwER, a double-blind, randomised, phase 3 study, evaluated the efficacy and safety of erenumab in adults with episodic migraine from Asia, the Middle East, and Latin America. Methods Randomised patients (N = 900) received monthly subcutaneous injections of placebo, erenumab 70 mg, or 140 mg (3:3:2) for 3 months. Primary endpoint was change from baseline in monthly migraine days at Month 3. Other endpoints included achievement of ≥50%, ≥75%, and 100% reduction in monthly migraine days, change in monthly acute migraine-specific medication treatment days, patient-reported outcomes, and safety assessment. Results At baseline, mean (standard deviation) age was 37.5 (9.9) years, 81.9% were women, and monthly migraine days was 8.2 (2.8). At Month 3, change from baseline in monthly migraine days (primary endpoint) was −3.1, −4.2, and −4.8 days for placebo, erenumab 70 mg, and erenumab 140 mg, respectively, with a statistically significant difference for erenumab versus placebo (P = 0.002 [70 mg], P < 0.001 [140 mg]). Both erenumab doses were also significantly superior to placebo on all secondary endpoints, including the proportion of patients achieving ≥50% reduction from baseline in monthly migraine days, change from baseline in monthly acute migraine-specific medication treatment days and change from baseline in the Headache Impact Test-6™ scores. The safety profile of erenumab was comparable with placebo; no new safety signals were observed. Conclusions This study of erenumab in patients with episodic migraine from Asia, the Middle East, and Latin America met all primary and secondary endpoints. A consistent numerical benefit was observed with erenumab 140 mg versus erenumab 70 mg across all efficacy endpoints. These findings extend evidence of erenumab’s efficacy and safety to patients under-represented in previous trials. ClinicalTrials.gov identifier: NCT03333109

scholarly journals Mortality in patients with atrial fibrillation with or without heart failure following hospital discharge

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Kartas ◽  
A Samaras ◽  
D Vasdeki ◽  
G Dividis ◽  
G Fotos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Primary Endpoint ◽  
Cox Regression ◽  
Cross Sectional ◽  
Tertiary Center ◽  
All Cause Mortality ◽  
Endpoint Event ◽  
Secondary Endpoints ◽  
Sectional Analysis

Abstract Background The association of heart failure (HF) with the prognosis of atrial fibrillation (AF) remains unclear. OBJECTIVES To assess all-cause mortality in patients following hospitalization with comorbid AF in relation to the presence of HF. Methods We performed a cross-sectional analysis of data from 977 patients discharged from the cardiology ward of a single tertiary center between 2015 and 2018 and followed for a median of 2 years. The association between HF and the primary endpoint of death from any cause was assessed using multivariable Cox regression. Results HF was documented in 505 (51.7%) of AF cases at discharge, including HFrEF (17.9%), HFmrEF (16.5%) and HFpEF (25.2%). A primary endpoint event occurred in 212 patients (42%) in the AF-HF group and in 86 patients (18.2%) in the AF-no HF group (adjusted hazard ratio [aHR] 2.27; 95% confidence interval [CI], 1.65 to 3.13; P&lt;0.001). HF was associated with a higher risk of the composite secondary endpoint of death from any cause, AF or HF-specific hospitalization (aHR 1.69; 95% CI 1.32 to 2.16 p&lt;0.001). The associations of HF with the primary and secondary endpoints were significant and similar for AF-HFrEF, AF-HFmrEF, AF-HFpEF. Conclusions HF was present in half of the patients discharged from the hospital with comorbid AF. The presence of HF on top of AF was independently associated with a significantly higher risk of all-cause mortality than did absence of HF, irrespective of HF subtype. Funding Acknowledgement Type of funding source: None

scholarly journals Nurse-based secondary preventive follow-up by telephone reduced recurrence of cardiovascular events: a randomised controlled trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna-Lotta Irewall ◽  
Anders Ulvenstam ◽  
Anna Graipe ◽  
Joachim Ögren ◽  
Thomas Mooe
Keyword(s):  
Randomised Controlled Trial ◽  
Primary Endpoint ◽  
Cardiovascular Events ◽  
Controlled Trial ◽  
Control Group ◽  
Coronary Syndrome ◽  
Secondary Endpoints ◽  
Randomised Controlled

AbstractEnhanced follow-up is needed to improve the results of secondary preventive care in patients with established cardiovascular disease. We examined the effect of long-term, nurse-based, secondary preventive follow-up by telephone on the recurrence of cardiovascular events. Open, randomised, controlled trial with two parallel groups. Between 1 January 2010 and 31 December 2014, consecutive patients (n = 1890) admitted to hospital due to stroke, transient ischaemic attack (TIA), or acute coronary syndrome (ACS) were included. Participants were randomised (1:1) to nurse-based telephone follow-up (intervention, n = 944) or usual care (control, n = 946) and followed until 31 December 2017. The primary endpoint was a composite of stroke, myocardial infarction, cardiac revascularisation, and cardiovascular death. The individual components of the primary endpoint, TIA, and all-cause mortality were analysed as secondary endpoints. The assessment of outcome events was blinded to study group assignment. After a mean follow-up of 4.5 years, 22.7% (n = 214) of patients in the intervention group and 27.1% (n = 256) in the control group reached the primary composite endpoint (HR 0.81, 95% CI 0.68–0.97; ARR 4.4%, 95% CI 0.5–8.3). Secondary endpoints did not differ significantly between groups. Nurse-based secondary preventive follow-up by telephone reduced the recurrence of cardiovascular events during long-term follow-up.

Prevalence and Risk Factors of Relapse in Patients with ANCA-Associated Vasculitis Receiving Cyclophosphamide Induction: A Systematic Review and Meta-analysis of Large Observational Studies

Rheumatology ◽  
2020 ◽  
Author(s):  
Peng He ◽  
Jin-ping Hu ◽  
Xiu-juan Tian ◽  
Li-jie He ◽  
Shi-ren Sun ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Baseline Serum ◽  
Anca Associated Vasculitis ◽  
Hazard Ratios ◽  
Post Hoc ◽  
Cumulative Probabilities ◽  
Relapse Rates

Abstract Background Clinical relapses are common in patients with ANCA-associated vasculitis (AAV). The aim of this systematic review was to estimate time-point prevalence and risk factors of relapse. Methods We searched PubMed, Embase, and Cochrane Library databases from their inception to March 30, 2020. Cohorts and post-hoc studies were included for the estimation of summary cumulative relapse rates (CRRs) and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Sensitivity and meta-regression analyses were also performed. Results Of the 42 eligible studies, 24 studies with 6236 participants were used for the pooled analyses of CRRs. The summary 1-year, 3-year, and 5-year CRRs were 0.12 (95% CI, 0.10–0.14), 0.33 (0.29–0.38), and 0.47 (0.42–0.52), respectively. In meta-regressions, the baseline age was positively associated with 1-year CRR. The proportion of granulomatosis with polyangiitis was positively associated with 5-year CRR. Twenty-eight studies with 5390 participants were used for the meta-analysis of risk factors for relapse, including a lower level of baseline serum creatine, proteinase 3 (PR3)-ANCA positivity at diagnosis, an ANCA rise, extrarenal organ involvement (including lung, cardiovascular, upper respiratory, and gastrointestinal involvement), intravenous (vs oral) cyclophosphamide induction, a shorter course of immunosuppressant maintenance, and maintenance with mycophenolate mofetil (vs azathioprine). Conclusions Our systematic review demonstrated that the 1-year, 3-year, and 5-year cumulative probabilities of relapse were ∼12%, 33%, and 47% in AAV patients receiving cyclophosphamide induction, respectively. Early identification of risk factors for relapse is helpful to the risk stratification of patients so as to achieve personalized treatment.

scholarly journals DAS181 Treatment of Severe Lower Respiratory Tract Parainfluenza Virus Infection in Immunocompromised Patients: A Phase 2 Randomized, Placebo-Controlled Study

2021 ◽  
Author(s):  
Roy F Chemaly ◽  
Francisco M Marty ◽  
Cameron R Wolfe ◽  
Steven J Lawrence ◽  
Sanjeet Dadwal ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Respiratory Tract ◽  
Primary Endpoint ◽  
Lower Respiratory Tract ◽  
Parainfluenza Virus ◽  
Controlled Study ◽  
Solid Organ ◽  
Immunocompromised Patients ◽  
Post Hoc Analysis ◽  
Post Hoc

Abstract Background There are no antiviral therapies for parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV. Methods Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment. Results A total of 111 patients were randomized to DAS181 (n = 74) or placebo (n = 37). CSS was achieved by 45.0% DAS181-treated patients in the SO stratum compared with 31.0% for placebo (P = .15), whereas patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with placebo (34.5%) at day 28 (P = .17). In a post hoc analysis of solid organ transplant, hematopoietic cell transplantation within 1 year, or chemotherapy within 1 year, more SO stratum patients achieved RTRA on DAS181 (51.8%) compared with placebo (15.8%) by day 28 (P = .012). Conclusions The primary endpoint was not met, but post hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation. Clinical Trials Registration. NCT01644877.

scholarly journals Lipoprotein(a) and Cardiovascular Outcomes after Revascularization of Carotid and Lower Limbs Arteries

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 257
Author(s):  
Marat V. Ezhov ◽  
Narek A. Tmoyan ◽  
Olga I. Afanasieva ◽  
Marina I. Afanasieva ◽  
Sergei N. Pokrovsky
Keyword(s):  
Primary Endpoint ◽  
Cardiovascular Events ◽  
Cardiovascular Outcomes ◽  
Lower Limbs ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Cox Regression Analysis ◽  
Lipoprotein A ◽  
Secondary Endpoints

Background: Despite high-intensity lipid-lowering therapy, there is a residual risk of cardiovascular events that could be associated with lipoprotein(a) (Lp(a)). It has been shown that there is an association between elevated Lp(a) level and cardiovascular outcomes in patients with coronary heart disease. Data about the role of Lp(a) in the development of cardiovascular events after peripheral revascularization are scarce. Purpose: To evaluate the relationship of Lp(a) level with cardiovascular outcomes after revascularization of carotid and lower limbs arteries. Methods: The study included 258 patients (209 men, mean age 67 years) with severe carotid and/or lower extremity artery disease, who underwent successful elective peripheral revascularization. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the composite of primary endpoint and repeated revascularization. Results: For 36-month follow-up, 29 (11%) primary and 128 (50%) secondary endpoints were registered. There was a greater risk of primary (21 (8%) vs. 8 (3%); hazard ratio (HR), 3.0; 95% confidence interval (CI) 1.5–6.3; p < 0.01) and secondary endpoints (83 (32%) vs. 45 (17%), HR, 2.8; 95% CI 2.0–4.0; p < 0.01) in patients with elevated Lp(a) level (≥30 mg/dL) compared to patients with Lp(a) < 30 mg/dL. Multivariable-adjusted Cox regression analysis revealed that Lp(a) was independently associated with the incidence of cardiovascular outcomes. Conclusions: Patients with peripheral artery diseases have a high risk of cardiovascular events. Lp(a) level above 30 mg/dL is significantly and independently associated with cardiovascular events during 3-year follow-up after revascularization of carotid and lower limbs arteries.

scholarly journals Blumgart Anastomosis After Pancreaticoduodenectomy. A Comprehensive Systematic Review, Meta-Analysis, and Meta-Regression

2021 ◽  
Author(s):  
Claudio Ricci ◽  
Carlo Ingaldi ◽  
Laura Alberici ◽  
Nico Pagano ◽  
Cristina Mosconi ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Postoperative Morbidity ◽  
Weighted Mean Difference ◽  
Meta Analysis ◽  
Random Effect ◽  
Reoperation Rate ◽  
Protective Role ◽  
Risk Difference ◽  
Number Needed To Treat ◽  
Secondary Endpoints

Abstract Background The superiority of Blumgart anastomosis (BA) over non-BA duct to mucosa (non-BA DtoM) still remains under debate. Methods We performed a systematic search of studies comparing BA to non-BA DtoM. The primary endpoint was CR-POPF. Postoperative morbidity and mortality, post-pancreatectomy hemorrhage (PPH), delayed gastric emptying (DGE), reoperation rate, and length of stay (LOS) were evaluated as secondary endpoints. The meta-analysis was carried out using random effect. The results were reported as odds ratio (OR), risk difference (RD), weighted mean difference (WMD), and number needed to treat (NNT). Results Twelve papers involving 2368 patients: 1075 BA and 1193 non-BA DtoM were included. Regarding the primary endpoint, BA was superior to non-BA DtoM (RD = 0.10; 95% CI: −0.16 to −0.04; NNT = 9). The multivariate ORs' meta-analysis confirmed BA's protective role (OR 0.26; 95% CI: 0.09 to 0.79). BA was superior to DtoM regarding overall morbidity (RD = −0.10; 95% CI: −0.18 to −0.02; NNT = 25), PPH (RD = −0.03; 95% CI −0.06 to −0.01; NNT = 33), and LOS (− 4.2 days; −7.1 to −1.2 95% CI). Conclusion BA seems to be superior to non-BA DtoM in avoiding CR-POPF.

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