Threshold For Non-inferiority Research Articles

Aspirin Discontinuation at 24 to 28 Weeks’ Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial

ABSTRACT Preeclampsia affects up to 4% of pregnancies and is marked by the development of hypertension and proteinuria after 20 weeks of gestation. Complications associated with the disorder include preterm birth, fetal growth restriction, placental abruption, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, seizures, and other end organ damage. Aspirin has been shown to reduce the incidence of preterm preeclampsia by 62%. However, it can also lead to peripartum bleeding. Screening for preeclampsia in the first trimester (11 to 13 weeks' gestation) can help identify up to 60% of pregnant individuals who will develop preterm preeclampsia. If preeclampsia screening is conducted during this first trimester, aspirin can be initiated earlier and discontinued earlier to mitigate the risk of peripartum bleeding. In addition, increased soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio is associated with preeclampsia weeks before its clinical onset. An sFlt-1:PlGF of ≤38 has been shown to accurately exclude preeclampsia in pregnant individuals with suspected disease. The aim of this study was to compare the effect of discontinuing aspirin in pregnant individuals at 24 and 28 weeks' gestation with a normal sFlt-1:PlGF ratio of ≤38 against those who continued aspirin treatment until 36 weeks of gestation. This was an open-label, randomized, noninferiority trial conducted at 9 maternity hospitals in Spain. Included were adult individuals with singleton pregnancies who had live births, were found to be at high risk of preeclampsia at the first-trimester screening, and a normal sFlt-1:PlGF between 24 and 28 weeks of gestation. Participants were randomly assigned 1:1 to discontinue aspirin (intervention group) or continue aspirin treatment (control group). The primary outcome was delivery due to preterm preeclampsia (before 37 weeks' gestation). Noninferiority was met if the higher 95% confidence interval (CI) for the difference in the incidences of preterm preeclampsia between the 2 groups was <1.9%. A total of 964 pregnant individuals, who were identified as high-risk for preterm preeclampsia and prescribed 150 mg of aspirin daily at bedtime, were eligible for the analysis. The rates of preterm preeclampsia in the intervention and control groups were 1.48% and 1.73%, respectively (absolute difference, −0.25% [95% CI, −1.86% to 1.36%]). In conclusion, the threshold for noninferiority was not met. In pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio of ≤38, discontinuing aspirin at 24 to 28 weeks' gestation was noninferior to continuing aspirin until 36 weeks to prevent preterm preeclampsia.

Endovascular thrombectomy or bridging therapy in minor ischemic stroke with large vessel occlusion

BackgroundWhether direct endovascular thrombectomy (EVT) is non-inferior to bridging therapy (intravenous thrombolysis [IVT] followed by EVT) in minor acute ischemic stroke due to large vessel occlusions (AIS-LVO) is not clear. Therefore, this study aimed to assess whether direct EVT is non-inferior to bridging therapy in minor AIS-LVO. Methods903 patients with acute ischemic stroke due to large vessel occlusion and National Institutes of Health Stroke Scale (NIHSS) score <6 receiving EVT treatment were enrolled at Bigdata Observatory Platform for Stroke of China in China from January 1, 2019, to December 31, 2020, with final follow-up on March 31, 2021. The primary efficacy endpoint was a favorable outcome defined as a modified Rankin Scale score of 0 to 2 at three months. In addition, there were three prespecified secondary efficacy endpoints, including symptomatic intracerebral hemorrhage (ICH), in-hospital mortality, and mortality by month 3. ResultsA total of 662 patients treated with direct EVT (age 65.9 ± 10.5 years, 71.5 % male, NIHSS score 2.4 [standard deviation {SD}. 1.8]) were compared to 241 bridging-treated patients (age 65.7 ± 10.8, 75.9 % female, NIHSS score 2.5 [1.8]). The rate of symptomatic ICH in the EVT group was lower than in the bridging group (4.2 % vs. 8.3 %; P = 0.02). The in-hospital mortality was not different between the two groups (EVT vs. bridging group: adjusted hazard ratio {HR}, 0.9 [95 % confidence interval {CI}, 0.5 to 1.9]; P = 0.93). There was no significant difference in 3-month poor functional outcome rate (EVT vs. bridging group: 17.1 % vs. 16.2 % [absolute difference, 0.9 % {95 % CI, −0.8 % to 2.4 %}, P = 0.75; adjusted hazard ratio {HR}, 1.0 {95 % CI, 0.6 to 1.7}, P = 0.83]) and mortality rate (13.0 % vs. 11.2 % [absolute difference, 1.5 % {95 % CI, −3.9 % to 6.8 %}, P = 0.47; adjusted HR, 1.1 {95 % CI, 0.8 to 1.9}, P = 0.55]) between those two groups. ConclusionAmong patients with minor AIS-LVO, direct EVT, compared with bridging therapy, met the prespecified statistical threshold for noninferiority for the 3-month prognosis.

Safety and Effectiveness of the SVELTE Fixed-Wire and Rapid Exchange Bioresorbable-Polymer Sirolimus-Eluting Coronary Stent Systems for the Treatment of Atherosclerotic Lesions: Results of the OPTIMIZE Randomized Study

[Figure: see text].

An automated computational image analysis pipeline for histological grading of cardiac allograft rejection.

AimAllograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologistsMethods and resultsThe study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The ‘Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader’ pipeline was trained using an interpretable, biologically inspired, ‘hand-crafted’ feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the ‘grade of record’, testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement [95% confidence interval (CI): 55.2–66.0%] with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0–65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4–68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3–64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P < 0.001).ConclusionThese results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.

Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke

<h3>Importance</h3> For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. <h3>Objective</h3> To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke. <h3>Design, Setting, and Participants</h3> Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020). <h3>Interventions</h3> A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. <h3>Main Outcomes and Measures</h3> The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was −10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. <h3>Results</h3> The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, −5.1% to ∞)<i>P</i>for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, −0.8%; 95% CI, −7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, −0.5%; 95% CI, −10.3% to 9.2%). <h3>Conclusions and Relevance</h3> Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold. <h3>Trial Registration</h3> Chinese Clinical Trial Registry:ChiCTR-IOR-17013568

Abstract CT211: EF-19 - A post-approval registry study of TTFields for the treatment of recurrent glioblastoma (GBM)

Abstract Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In phase 3 studies leading to FDA approvals, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide, and achieved comparable survival outcome to best standard of care (BSC) when used as monotherapy in recurrent GBM. The aim of the EF-19 study was to confirm the efficacy of TTFields versus BSC for recurrent GBM in the post-approval real-life setting. Method: This non-inferiority, prospective, non-randomized, post approval registry trial enrolled 192 recurrent GBM patients (&amp;gt;21 years, KPS &amp;gt; 70). All patients were treated with TTFields (200 kHz, &amp;gt;18h/day). Eligibility criteria included histological diagnosis of GBM, past treatment with the Stupp protocol for the primary disease and radiological evidence of progression in the supratentorial region. The primary endpoint was overall survival (OS); secondary endpoints included OS in the per protocol (PP) population (&amp;gt;1 course of TTFields or BSC in each respective arm), time to treatment failure and incidence of adverse events. The TTFields patient registry data were compared to OS of all 117 recurrent GBM patients in the BSC group of the EF-11 pivotal trial (Stupp R., et al., EJC 2012). The sample size of 192 patients (10% loss to follow up) was determined based on non-inferiority log-rank test with a two-sided alpha level of 0.05 and a power of 80%, comparing time to event (i.e., death) between patients treated with TTFields and BSC. The analysis was based on true hazard ratio (HR) of 1.0 comparing TTFields to control with an upper one-sided 95% confidence bound of HR is not exceeding 1.375. Result: Median OS in patients treated with TTFields versus EF-11 BSC was 7.4 vs. 6.4 months, p=0.053; HR = 0.64 (95%CI 0.46-0.91, Cox-test P=0.012). In the PP population, the median OS with TTFields versus EF-11 BSC was 8.1 months vs. 6.5 months, respectively; p=0.045; HR 0.65. The results show a significant superiority HR of overall survival between the ITT groups, as superiority 95% confident interval upper limit of the HR was lower than the pre-defined threshold for non-inferiority for interval bound of 1.375. The overall incidence of adverse event was lower in the TTFields arm (67% vs. 95%) vs. EF-11 BSC arm. The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9)) compared to the BSC arm (1.6 months; 95% CI 1.1, 1.9); HR=0.53 (95% CI 0.41, 0.68, p&amp;lt;0.0001). Skin AE was the most frequently reported AEs in TTFields-treated patients; No unexpected adverse events were reported with TTFields. Conclusion: The EF-19 confirmed the effectiveness and safety of TTFields as monotherapy in recurrent GBM. Citation Format: Jay-Jiguang Zhu, Robert T. O'Donnell, Zvi Ram. EF-19 - A post-approval registry study of TTFields for the treatment of recurrent glioblastoma (GBM) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT211.

EF-19, a post-approval registry study of tumor treating fields (TTFields) in recurrent glioblastoma (rGBM).

e14536 Background: Tumor Treating Fields (TTFields) are an anti-mitotic non-invasive therapy of low intensity alternating electric fields delivered to the tumor via a portable medical device. In phase 3 studies that led to FDA approvals, TTFields plus maintenance temozolomide significantly extended survival in newly diagnosed GBM, and achieved comparable survival outcome to best standard of care (BSC) as monotherapy in recurrent GBM (rGBM). The EF-19 study aimed to confirm efficacy of TTFields vs BSC in rGBM in post-approval real-life setting. Methods: This non-inferiority, prospective, non-randomized, post approval registry trial enrolled 192 rGBM patients (&gt;21 yrs, KPS &gt; 70). Patients were treated with TTFields (200 kHz, &gt; 18h/day). Eligibility criteria: histologic GBM, past treatment per Stupp protocol for primary disease and radiological evidence of progression in the supratentorial region. Primary endpoint was overall survival (OS); secondary endpoints were OS in the per protocol (PP) population ( &gt; 1 course of TTFields or BSC in each respective arm), time to treatment failure and adverse events. The TTFields patient registry data were compared to OS of all 117 rGBM patients in the BSC group of the EF-11 trial (Stupp R, EJC 2012). The sample size of 192 patients (10% loss to follow up) was based on non-inferiority log-rank test with a two-sided alpha level of 0.05 and a power of 80%, comparing time to event (i.e., death) between patients treated with TTFields and BSC. The analysis was based on true hazard ratio (HR) of 1.0 comparing TTFields to control with an upper one-sided 95% confidence bound of HR not exceeding 1.375. Results: Median OS with TTFields versus EF-11 BSC was 7.4 vs. 6.4 months, p = 0.053; HR = 0.64 (95%CI 0.46-0.91, Cox-test P = 0.012). Median OS (PP population) with TTFields versus EF-11 BSC was 8.1 months vs. 6.5 months; p = 0.045; HR 0.65. The results showed a significant superiority in HR of OS between the 2 groups, as the 95% confident interval upper limit of the HR was lower than the pre-defined threshold for non-inferiority for interval bound of 1.375. The overall incidence of adverse event was lower with TTFields than EF-11 BSC (67% vs. 95%). The median time to treatment failure was longer in the TTFields arm (3.3 months (95% CI 2.6, 3.9) versus BSC arm (1.6 months; 95% CI 1.1, 1.9); HR = 0.53 (95% CI 0.41, 0.68, p &lt; 0.0001). Skin AE was the most frequently reported AEs in TTFields arm; no unexpected adverse events were reported with TTFields. Conclusions: The results of the EF-19 registry study confirm the effectiveness and safety of TTFields monotherapy in rGBM.

Lower versus traditional treatment threshold for neonatal hypoglycaemia: No difference between the groups at 18 months of age, awaiting long-term outcomes.

Neonatal hypoglycaemia has long been a medical conundrum. The mere definition and operational threshold with which to offer treatment has long been and continues to be debated. Severe and symptomatic hypoglycaemia negatively impacts long-term neurodevelopment. How to balance treatment without risking adverse consequences and without overutilization of health care resources are discussed often. As a result, this research study sets out to challenge the dogma of the required treatment at glucose <47 mg/dL. One aspect that distinguishes this study from others was its unique clinical design. While most other studies are retrospective, this study was a prospective, randomized, non-inferiority study assessing the current operational threshold for hypoglycaemia treatment with a lower threshold. The study allowed for neurodevelopmental outcomes <0.5 standard deviations below the mean, as a threshold for non-inferiority. Given one standard deviation from the mean is considered normal, this was a reasonable threshold. Additionally, the study was able to achieve its goal of 85% neurodevelopmental follow-up at age 18 months, which is impressive for a condition that is usually short-term and often viewed as benign. There were a few critical aspects of this study. First, it was underpowered to assess infants of diabetic mothers. Second, aside from the treatment threshold, there was no defined protocol for how to treat hypoglycaemia, and it was left to provider discretion despite wide practice variations. Lastly and most importantly, follow-up at 18 months of age is likely too soon to detect differences in neurodevelopmental outcomes; therefore, most follow-up studies focus on 24 months of age or higher. The CHYLD studies by McKinlay et al found no difference in neurodevelopmental outcomes between neonate with hypoglycaemia (defined as glucose <47 mg/dL) and those without at 24 months of age, but did find differences in executive and visual-motor functioning at 4.5 years of age.1, 2 Several additional studies with longer-term follow-up have shown differences between cohorts with and without neonatal hypoglycaemia. For instance, Wickström et al (2018) showed evidence of motor and cognitive delay at 2-6 years of age-associated with moderate hypoglycaemia (defined as glucose <40 mg/dL).3 Kaiser used 4th-grade standardised testing to assess 10-year follow-up and found an association with decreased literacy and mathematics scores with a single incidence of glucose <45 mg/dL and even further disparity at lower thresholds of <40 mg/dL and <35 mg/dL.4 A systematic review by Shah in 2019 concluded neonatal hypoglycaemia is associated visual-motor impairment and executive dysfunction in early-childhood (2-5 years of age) and neurodevelopmental impairment and low literacy in mid-childhood (6-11 years of age).5 Given this evidence, it is reasonable to conclude while this study showed no difference at 18-month follow-up that longer-term follow-up might show differences. As this study completed in 2011, it would be interesting to see whether a 4- to 6-year follow-up is assessed, and if so, what the results show. In conclusion, while it may be too soon to instil practice changes based on the results of this study, there is potential if longer-term follow-up can show similar results. https://ebneo.org/2020/04/threshold-for-neonatal-hypoglycemia/ None.

1877PD - Prevalence and prognostic effect of high tumor mutation burden (TMB-H) across multiple less common solid cancers using a real-world dataset

BackgroundLittle is known about the prognostic effect of TMB-H among patients with less common cancers who did not receive an immunotherapy (IO). MethodsThe de-identified Flatiron Health-Foundation Medicine (FMI) Clinico-Genomic Database was used to select patients (pts) with any of 10 solid cancers (Table). 109 Pts with confirmed microsatellite instability-high (MSIH) cancers were excluded, of which 101 pts were endometrial cancer. TMB-H was defined as≥10 mutations per megabase (Mut/Mb) with an additional analysis using a cutoff of 13 Mut/Mb. For overall survival (OS) analysis, Pts with IO were excluded if start of IO earlier than or equal to FMI report date (69 pts), or censored if start of IO later than FMI report date (243 pts). OS was analyzed using Kaplan-Meier method and Cox proportional hazard model, adjusting for age, gender, cancer types, practice type and albumin. A non-inferiority test of TMB-H having longer OS than TMB-low (-L) was carried out with a prespecified hazard ratio (HR) of 0.75. ResultsOf the 2,589 pts (table), average age at diagnosis was 64 years and 65% were female. Median TMB was 2.6 Mut/Mb overall, ranged from 1.7 (Meso, salivary, thyroid) to 8.7 (SCLC) Mut/Mb. Overall 12.8% were TMB-H with the highest in SCLC (40.0%) and lowest in meso (1.2%). The adjusted HR (AHR) of TMB-H vs. -L was 0.94 (95% CI: 0.77-1.13) for OS from FMI report date, which met the prespecified threshold for non-inferiority by rejecting the null hypothesis. The AHR was 0.84 (0.67-1.05) using alternative cutoff of 13 Mut/Mb. Comparable results were observed when including MSI-H pts and calculating OS from 1st observed antineoplastic treatment date.Table: 1877PDTable: 1877PDNTMB-HOS (month, 95%CI)HRadjustPadjustn%TMB-HTMB-LTotal2,58933212.88.4 (7.4; 11.4)10.5 (9.5; 11.5)0.94 (0.77; 1.13)0.491SCLC30512240.06.4 (5.4; 7.5)7.4 (5.5; 10.5)1.03 (0.74; 1.44)0.863Neuroendocrine1644829.310.4 (6.4; NA)6.4 (4.5; 10.5)0.83 (0.48; 1.44)0.506Cervical1141714.9NA (6.4; NA)7.4 (4.4; 11.5)0.32 (0.08; 1.31)0.113Anal1251713.67.4 (2.5; NA)7.5 (5.5; 15.4)0.84 (0.40; 1.79)0.659Vulvar30413.38.5 (0.5; NA)6.5 (2.5; NA)1.18 (0.22; 6.29)0.848Salivary1692213.04.5 (3.5; NA)15.5 (10.5; 21.5)1.20 (0.48; 2.99)0.691Endometrial5906611.211.4 (8.5; 26.5)13.5 (11.5; 15.4)1.15 (0.75; 1.75)0.522Biliary706284.011.5 (7.4; NA)8.4 (7.4; 10.4)0.65 (0.35; 1.19)0.162Thyroid22362.710.2 (1.5; NA)27.5 (21.5; NA)1.64 (0.39; 6.96)0.502Meso16321.2NA12.5 (8.5; 15.5)-0.997 ConclusionsThere is a wide range of TMB among these cancers. Non-inferiority testing and HR estimates comparing OS for TMB-H (≥10 Mut/Mb) vs. -L did not support an effect of TMB on OS in the absence of IO for these cancers. Further research is needed to explore whether the prognostic effect of TMB varies by tumor type or threshold. Legal entity responsible for the studyMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. DisclosureD. Backenroth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Flatiron Health Inc. C. Shao: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co. G. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. L. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co.. S.K. Pruitt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. E. Castellanos: Full / Part-time employment: Flatiron Health Inc.. G.M. Frampton: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. K.R. Carson: Full / Part-time employment: Flatiron Health Inc.. T. Snow: Full / Part-time employment: Flatiron Health Inc.. G. Singal: Full / Part-time employment: Foundation Medicine. D. Fabrizio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. B.M. Alexander: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine. F.J. Jin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. W. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc..

1102-P: High vs. Standard Starting Dose of Insulin Glargine 100 U/ml in Patients with Overweight/Obesity and Type 2 Diabetes Uncontrolled with Oral Antidiabetic Drugs in China: A Multicenter, Open-Label Randomized Controlled Trial

With type 2 diabetes (T2D) progression, patients require insulin, but insufficient titration often leads to poor glycemic control. A higher insulin starting dose may reduce the optimal dose deficit, but whether this procedure increases hypoglycemia risk is unknown. This open-label, multicenter trial (NCT02836704) evaluated safety and efficacy of a high (0.3 U/kg) vs. standard (0.2 U/kg) starting dose of glargine 100 U/ml (Gla-100) followed by titration over 16 weeks to achieve self-monitored FBG 4.4-5.6 mmol/L using the same algorithm in each group. Overall, 892 patients with overweight/obesity (BMI 25-40 kg/m2) and uncontrolled T2D (HbA1c 7.5-11.0%; lab FPG &amp;gt;9.0 mmol/L) on stable doses of 2-3 OADs were randomized to receive a high (n=444) or standard (n=448) starting dose of Gla-100. At week 16, 92% of patients completed the study and 866 were analyzed. The primary endpoint (percentage of patients with ≥1 confirmed hypoglycemia, BG &amp;lt;3.9 mmol/L) met the pre-specified threshold (upper bound 95% CI &amp;lt;10%) for non-inferiority of Gla-100 0.3 U/kg vs. 0.2 U/kg with 11.0% and 8.6% in the respective groups (log-binomial regression estimated difference 2.1%; 95% CI: −1.68%, 5.89%). At week 16, symptomatic (9.8% vs. 7.0%, p=0.13) and nocturnal hypoglycemia (2.7% vs. 1.2%, p=0.10), percentage of patients achieving HbA1c &amp;lt;7.0% without hypoglycemia (37.1% vs. 37.1%), and percentage of patients achieving lab FPG targets &amp;lt;5.6 mmol/L (15.9% vs. 16.3%), &amp;lt;6.1 mmol/L (27.6% vs. 26.1%), or &amp;lt;7.0 mmol/L (48.8% vs. 48.3%) were all similar in both groups. However, time to achieve first self-monitored FBG &amp;lt;5.6, &amp;lt;6.1, or &amp;lt;7 mmol/L was 6, 9, and 7 days shorter in the 0.3 U/kg group (all p&amp;lt;0.01). In conclusion, among patients with overweight/obesity and T2D, a higher Gla-100 starting dose was as safe as a standard Gla-100 starting dose and achieved FBG targets earlier during the course of therapy. Disclosure L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis AG, Roche Pharma, Sanofi. H. Wan: None. B. Wen: None. X. Wang: None. J. Wang: Research Support; Self; Sanofi. R. Bian: None. W. Pang: None. W. Feng: Employee; Self; Sanofi. X. Zhang: None. N. Cui: Employee; Self; Sanofi. Funding Sanofi China

Evaluating the User Performance and Experience with a Re-Engineered 4mm × 32G Pen Needle: A Randomized Trial with Similar Length/Gauge Needles.

IntroductionSince insulin pens were first introduced in 1985, many advances have been made in pen needles (PNs). In this study we evaluated patient-reported outcomes of an investigational newly re-engineered 4 mm × 32G PN, the BD Nano™ 2nd Gen (also known by its “PRO” brand extension in many markets outside of the USA). In place of a conventional cylindrical posted hub, the investigational PN’s hub is contoured with an expanded surface area. The investigational PN also includes a redesigned inner shield that includes tactile ridges and a remodeled outer cover with improved proportions and attachment grips.MethodsThis was a multi-site, prospective, open-label, two-period crossover trial. Individuals with type 1 and type 2 diabetes using 32G PNs of ≤ 6 mm in length for ≥ 4 months were eligible. Subjects using 31G PNs of a similar length were eligible after a 2-week wash-in period. Subjects were assigned to one of four groups, with each group using a commercially available PN to which the investigational PN was compared. Each of the two study periods were 15 days: one with the investigational PN and the other with a comparator PN. After completing both study periods, subjects compared experiences between the two PN types. A 150-mm comparative visual analog scale (VAS) was used to evaluate overall preference (primary endpoint) and several secondary endpoints, including overall comfort, injection pain, and ease of use. Data from the four PN groups were combined after poolability was verified. Subgroup analyses were also conducted on each PN group. For VAS responses, a two-sided 95% confidence interval (CI) was calculated for average rating. Threshold for non-inferiority or superiority was established at the lower bound CI of > − 10 mm or > 0 mm, respectively.ResultsAt baseline, average age of subjects was 55.6 years; 51.6% were female; and 85.1% has type 2 diabetes mellitus. Average diabetes duration was 14.2 years, and average duration of injecting was 7.8 years. The investigational PN demonstrated superiority for all outcomes, both primary and secondary, for all groups combined (p < 0.05).ConclusionsThe investigational PN was rated as being overall preferred, more comfortable, less painful, and easier to use when compared to comparator PNs of similar gauge and length, in all groups combined.Clinical Trial RegistrationClinicaltrials.gov (NCT03267264).FundingBD (Becton, Dickinson, and Company).

Comparison of two breast cancer survivorship treatment summary and care plan (TSCP) documents.

49 Background: The 2005 Institute of Medicine report recommended providing a cancer TSCP, but barriers including time needed to complete these documents led to limited implementation. In 2014, in order to facilitate delivery, ASCO released a streamlined version of a TSCP. The current prospective, randomized study compares a Breast Cancer ASCO 2014 derived template (concise TSCP) with a facility derived Breast Cancer TSCP template based on the “old” ASCO version and NCCN guideline recommended elements (detailed TSCP). Methods: Female breast cancer survivors who completed therapy at Gundersen Health System were randomized between a concise TSCP and a detailed TSCP. Subjects received a survey prior to their survivorship visit assessing their baseline knowledge of their breast cancer diagnosis and treatment (pre visit knowledge). After the visit, participants completed the same survey (post visit knowledge) and a satisfaction survey. Pre and post visit knowledge survey scores, patient satisfaction scores and time needed to complete the TSCP were compared between the two study groups. Results: Both TSCP groups showed significant improvement in patient-specific disease and treatment knowledge scores (% of applicable knowledge questions answered correctly) after their survivorship visit. There was no significant difference between the concise and detailed groups’ pre-visit knowledge score (mean 78% vs. 79%, p=0.88). Calculated difference between the groups’ post knowledge scores met the pre-determined threshold for non-inferiority (p=0.013). Conclusions: Our study demonstrates the value of a cancer TSCP and Survivorship visit in improving breast cancer survivors’ knowledge of their disease characteristics and treatment. The concise version was found to be non-inferior to the detailed TSCP in terms of patient knowledge and satisfaction and required less time to complete. These results assist us and other institutions in choosing a more streamlined version of TSCP without compromising patient knowledge or satisfaction. [Table: see text]

Randomized clinical trial of a single versus a double dose of 13-valent pneumococcal conjugate vaccine in adults 55 through 74 years of age previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

IntroductionIn older adults, prior administration of 23-valent pneumococcal polysaccharide vaccine (PPSV23) blunts the opsonophagocytic antibody (OPA) response to subsequent administration of 13-valent pneumococcal conjugate vaccine (PCV13). To determine whether a higher dose of PCV13 could mitigate this effect in adults 55 through 74 years of age, we compared OPA responses to a double dose of PCV13 in persons previously vaccinated with PPSV23 with responses to a single dose of PCV13 in previously vaccinated persons, and with a single dose in PPSV23 naïve persons. MethodsSubjects previously vaccinated with PPSV23 were randomly assigned to receive either a single injection or two concurrent injections of 0.5 mL PCV13. Naïve subjects received a single injection of 0.5 mL PCV13. Serotype-specific OPA responses to 12 of the PCV13 serotypes were assessed on samples collected on Day 29 and Day 181. Comparisons of the OPA titers between study groups were based on the lower bound of the 95% confidence interval of the log geometric mean ratio to define superiority (>1) and non-inferiority (>0.5). ResultsAt Day 29, the OPA responses to one dose in previously vaccinated (n = 284) versus one dose in naïve subjects (n = 311) achieved the threshold for non-inferiority for only 3 of the 12 serotypes. In previously vaccinated subjects, responses to a double dose (n = 288) versus a single dose met the threshold for superiority for 7 serotypes. The responses to a double dose in previously vaccinated subjects versus a single dose in naïve subjects met the threshold for non-inferiority for 9 serotypes. ConclusionsThere is a dose response to PCV13 in older adults and the higher response to a double dose in previously vaccinated adults is non-inferior to that of a single dose in naïve adults for 9 of the 12 PCV13 serotypes evaluated.

Reliable Rapid Assay for Gonorrhea and Chlamydia in the Emergency Department

BackgroundChlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are common sexually transmitted infections seen in the emergency department (ED). Due to an inability to reliably make accurate diagnosis by physical examination, concern for unreliable follow-up, and current delays in diagnostic nucleic acid amplification testing (NAAT), presumptive treatment active against CT and NG, as described by Centers for Disease Control clinical practice guidelines, is often performed. ObjectivesThe purpose of this study was to determine whether a rapid, urine NAAT performed in the ED is noninferior in its diagnostic sensitivity compared with a traditional, swab NAAT assay. MethodsWe performed a prospective, noninferiority study comparing two U.S. Food and Drug Administration-approved NAAT assays for CT and NG: a 90-min rapid assay, the Xpert CT/NG Assay (Cepheid, Sunnyvale, CA) using a urine sample vs. a traditional assay, the Aptima Combo 2 Assay (Gen-Probe Incorporated, San Diego, CA) using a swab sample. This study was registered on Clinicaltrials.gov (NCT02386514). ResultsA total of 1162 patient samples were included in the primary analysis. We observed excellent kappa agreement between assays: NG for men, 1.00 (95% confidence interval [CI] 1.00–1.00); NG for women, 0.87 (95% CI 0.79–0.94); CT for men, 0.81 (95% CI 0.59–1.00); and CT for women: 0.85 (95% CI 0.80–0.90), as well as excellent negative and positive predictive values for the rapid assay. ConclusionAlthough the rapid Xpert CT/NG assay's diagnostic sensitivity did not meet our prespecified threshold for noninferiority, the diagnostic characteristics are robust enough to fit into a management pathway that may reduce unnecessary antibiotic use. There may be an opportunity to utilize the rapid Xpert CT/NG assay to improve accuracy of treatment in the ED.

Low-residue breakfast during the preparation for colonoscopy using a polyethylene glycol electrolyte solution: a randomised non-inferiority trial

GoalsTo test the hypothesis that the use of a low-residue breakfast (LRB) the day prior to colonoscopy was not inferior to consuming clear fluids alone (CFD) in patients undergoing outpatient...

Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial

The mainstay of treatment for Gaucher's disease type 1 is alternate-week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase. In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged ≥18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of four; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008-005223-28. Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference -8·8%; 95% CI -17·6 to 4·2). The lower bound of the 95% CI of -17·6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity). Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option. Genzyme, a Sanofi company.

Setting a high threshold for noninferiority: Mesalamine and budesonide in Crohnʼs disease

Setting a high threshold for noninferiority: Mesalamine and budesonide in Crohnʼs disease

Randomized Trial of Time-Limited Interruptions of Protease Inhibitor-Based Antiretroviral Therapy (ART) vs. Continuous Therapy for HIV-1 Infection

BackgroundThe clinical outcomes of short interruptions of PI-based ART regimens remains undefined.MethodsA 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load <50 copies/ml and CD4 T cell count >450 cells/µl on stavudine (or zidovudine), lamivudine and lopinavir/ritonavir. Subjects were randomized to a) sequential 2, 4 and 8-week ART interruptions or b) continuous ART (cART). Primary analysis was based on the proportion of CD4 count >350 cells(c)/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints.ResultsThe proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: −0.16, 23.1). No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm.ConclusionWe are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur.Trial RegistrationClinicalTrials.gov NCT00100646