Non-inferiority Phase Research Articles

Fibrinogen Concentrate Vs. Cryoprecipitate for Acquired Hypofibrinogenemia in Cardiac Surgery — the FIBRES Study

Introduction: Cardiac surgery involving cardiopulmonary bypass (CPB) is associated with coagulopathy and excessive bleeding. This often requires the transfusion of large volumes of allogeneic blood products and is linked to an increased risk of adverse outcomes. A primary cause of coagulopathy is acquired hypofibrinogenemia; when fibrinogen levels drop below 1.5-2 mg/L, fibrinogen supplementation is required to maintain hemostasis. The FIBrinogen REplenishment in Surgery (FIBRES) study aims to compare the standard intervention, cryoprecipitate, with a new highly purified, double virus-inactivated human fibrinogen concentrate.Methods: The FIBRES study (NCT03037424) is a pragmatic, multicenter, active-control, randomized, single-blinded, non-inferiority phase 3 trial in adult patients undergoing cardiac surgery with CPB. The study will enroll patients with clinically significant bleeding associated with acquired hypofibrinogenemia. Patients for whom fibrinogen supplementation is ordered within 24 hours of surgery will be randomized to receive fibrinogen concentrate (4 g; Fibryga; Octapharma) or cryoprecipitate (10 units; dose equivalent to 4 g fibrinogen concentrate) (Figure 1). All randomized patients will receive fibrinogen supplementation as clinically indicated. Owing to the emergency nature of the clinical setting, patient consent at the point of randomization will be waived, with written informed consent obtained within 24-48 hours thereafter. The primary outcome is total allogeneic blood products (red blood cells, plasma, platelets) administered within the first 24 hours of surgery. Secondary outcomes include blood product use within 7 days, incidence of major bleeding within 24 hours, fibrinogen levels, and adverse events (AEs) and serious AEs within 28 days. Enrolment of 1,200 patients will provide >90% power to demonstrate non-inferiority, assuming a 20% non-inferiority margin, ≥550 patients per group, and an approximate 10% drop-out rate. One pre-planned interim analysis will be conducted after data are available for 600 evaluable patients with the option to stop early for futility or overwhelming efficacy. The pragmatic design and treatment algorithm align with standard practice, aiding adherence and generalizability.Results: To date, 530 patients have been treated across 11 sites. An IDMEAC review of safety has been performed every 100 patients enrolled, with the recommendation to continue as planned each time. The study is expected to complete in late 2018, with results available in early 2019.Conclusions: The FIBRES study is the largest randomized study to date of fibrinogen concentrate versus cryoprecipitate in adult cardiac surgical patients, an under-studied yet high-risk population. Non-inferiority of the new fibrinogen concentrate would support its use for patients developing acquired hypofibrinogenemia during cardiac surgery. Results from the FIBRES study are likely to improve care for cardiac surgical patients experiencing significant bleeding. DisclosuresKarkouti:Octapharma US: Research Funding.

Overview of the pathological results and treatment characteristics in the first 1000 patients randomized in the SERC trial: axillary dissection versus no axillary dissection in patients with involved sentinel node

BackgroundThree randomized trials have concluded at non inferiority of omission of complementary axillary lymph node dissection (cALND) for patients with involved sentinel node (SN). However, we can outline strong limitations of these trials to validate this attitude with a high scientific level. We designed the SERC randomized trial (ClinicalTrials.gov, number NCT01717131) to compare outcomes in patients with SN involvement treated with ALND or no further axillary treatment. The aim of this study was to analyze results of the first 1000 patients included.MethodsSERC trial is a multicenter non-inferiority phase 3 trial. Multivariate logistic regression analysis was used to identify independent factors associated with adjuvant chemotherapy administration and non-sentinel node (NSN) involvement.ResultsOf the 963 patients included in the analysis set, 478 were randomized to receive cALND and 485 SLNB alone. All patient demographics and tumor characteristics were balanced between the two arms. SN ITC was present in 6.3% patients (57/903), micro metastases in 33.0% (298), macro metastases in 60.7% (548) and 289 (34.2%) were non eligible to Z0011 trial criteria.Whole breast or chest wall irradiation was delivered in 95.9% (896/934) of patients, adjuvant chemotherapy in 69.5% (644/926), endocrine therapy in 89.6% (673/751) and the proportions were similar in the two arms. The overall rate of positive NSN was 19% (84/442) for patients with cALND. Crude rates of positive NSN according to SN status were 4.5% for ITC (1/22), 9.5% for micro metastases (13/137), 23.9% for macro metastases (61/255) and were respectively 29.36% (64/218), 9.33% (7/75) and 7.94% (10/126) when chemotherapy was administered after cALND, before cALND and for patients without chemotherapy.ConclusionThe main objective of SERC trial is to demonstrate non inferiority of cALND omission. A strong interaction between timing of cALND and chemotherapy with positive NSN rate was observed.Trial registrationThis study is registered with ClinicalTrials.gov, number NCT01717131 October 19, 2012.

1703P - Incidence of hypocalcemia in a non-inferiority phase III trial assessing prevention of symptomatic skeletal events (SSE) with denosumab (DN) administered every 4 weeks (q4w) versus every 12 weeks (q12w): SAKK 96/12 (REDUSE)

1703P - Incidence of hypocalcemia in a non-inferiority phase III trial assessing prevention of symptomatic skeletal events (SSE) with denosumab (DN) administered every 4 weeks (q4w) versus every 12 weeks (q12w): SAKK 96/12 (REDUSE)

Development of New Formulations of Biologics: Expectations, Immunogenicity, and Safety for Subcutaneous Trastuzumab.

Subcutaneous (SC) trastuzumab has long been approved as a cancer treatment for early and advanced HER2-positive (HER2+) breast cancer by both the European Medicines Agency (EMA) and Agência Nacional de Vigilância Sanitária (ANVISA), the Brazilian National Health Surveillance Agency. A pivotal non-inferiority phase III trial, which aimed to provide a more convenient and cost-effective treatment in the HER2+ breast cancer neoadjuvant setting, showed that the SC group met prespecified efficacy endpoints and the SC formulation was considered as safe as the intravenous (IV) formulation. Considering the recent approval of several biosimilars, new SC formulations are also an interesting manufacturer strategy as these drugs can obtain patent protection. Despite being considered non-inferior to the IV formulation of trastuzumab, in clinical development, the SC formulation elicited higher immunogenicity, mainly related to overall anti-drug antibodies (ADAs); however, this finding was classified as clinically non-significant. In this article, we explore different aspects of the benefits and risks of the SC trastuzumab formulation according to published data.

Helicobacter pylori eradication in Mexico with a levofloxacin-based scheme versus standard triple therapy: Results from an open-label, randomized, noninferiority phase IIIb trial

Introduction and aimsHelicobacter pylori (H. pylori) infection remains the leading cause of several gastroduodenal diseases. Despite the fact that multiple antibiotic regimens have been used to change its associated morbidity and mortality, the prevalence of this bacterial infection continues to be disproportionately high worldwide, mainly due to antibiotic resistance. To assess the noninferiority efficacy and safety of 210-day triple regimens on H. pylori eradication, we evaluated clarithromycin 500mg, lansoprazole 30mg, and amoxicillin 1g, all bid (standard triple therapy or CLA, Group 1) vs. pantoprazole 80mg, levofloxacin 500mg and azithromycin 500mg, all od (PLA, Group 2). Both regimens were compared in treatment-naïve patients. Materials and methodsAn open label phase IIIb randomized and noninferiority trial comparing CLA vs. PLA was carried out for a 10-day period, within the time frame of June 2012 and March 2014. Eradication was verified with 13C-urea breath testing. Gastric biopsies were tested for fluorescence in situ hybridization (FISH)-clarithromycin resistance prior to any antibiotic administration. Efficacy and safety results were analyzed according to the noninferiority methodological approach. ResultsFrom the 227 H. pylori positive subjects that were randomized, 194 were finally analyzed as per-protocol. The group 2 eradication rate was 63% and was noninferior to the group 1 eradication rate of 58.5% (upper limit 95% CI: 0.11608; below the noninferiority margin: 0.1200). FISH clarithromycin-resistance was found in 28.2% of the cases. Adverse events, all minor and self-limited, were significantly higher in group 1 than in group 2 (86 vs. 65.4%; p=0.001). ConclusionsFirst-line H. pylori eradication with pantoprazole/levofloxacin/azithromycin combination therapy is as effective as the standard triple therapy, with better tolerability and easier dosing. Clarithromycin resistance should be considered when selecting antibiotics in Helicobacter pylori eradication treatments.ClinicalTrials.gov identifier NCT02726269.

Non-Antibiotic Herbal Therapy (BNO 1045) versus Antibiotic Therapy (Fosfomycin Trometamol) for the Treatment of Acute Lower Uncomplicated Urinary Tract Infections in Women: A Double-Blind, Parallel-Group, Randomized, Multicentre, Non-Inferiority Phase III Trial

Introduction: This randomized, controlled, Phase III non-inferiority clinical trial aimed to determine whether herbal therapy with Canephron® N (BNO 1045) is non-inferior to fosfomycin trometamol (FT) in treating acute lower uncomplicated urinary tract infections (uUTIs). Materials and Methods: Women aged 18–70 years with typical symptoms of newly diagnosed acute lower uUTIs were randomized to BNO 1045 (n = 325) or FT (n = 334), with corresponding matched placebo. The primary endpoint was the proportion of patients who received additional antibiotics (ABs) to treat uUTIs between Days 1 and 38 ±3. Results: Between Days 1 and 38, 238 (83.5%) patients in the BNO 1045 group and 272 (89.8%) patients in the FT group received no additional ABs. At a 15% non-inferiority margin, BNO 1045 was non-inferior to FT in treating uUTIs (non-AB rate difference: –6.26%; 95% CI –11.99 to –0.53%; 2-sided p = 0.0014). Adverse event rates were similar between groups, with higher rates of gastrointestinal disorders in the FT group and pyelonephritis in the BNO 1045 group. During the trial, no patient died or discontinued due to a treatment-related adverse event. Conclusions: BNO 1045 has the potential to reduce outpatient use of ABs for uUTIs and thus may have a significant impact on antimicrobial stewardship strategies. Trial registration: NCT02639520, EudraCT number 2013-004529-99.

Noninferiority of three months versus six months of oxaliplatin-based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

The eagerly awaited results of the multi-continental International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project have recently been presented at major oncological meetings. The 3-year disease-free survival (DFS) was presented for 12,834 Stage III colon cancer patients in a pooled analysis of 6 individual noninferiority phase III randomized trials, all investigating three versus six months of oxaliplatin-based adjuvant therapy. Noninferiority (NI) could not be demonstrated for the whole population as the DFS hazard ratio (HR) of 1.07 with its 95% CI of 1.00-1.15 crossed the postulated NI boundary of 1.12. However, there was an expected reduction in the incidence of specific side effects with the three months treatment. NI could be demonstrated for the T3N1 subgroup (∼60% of patients, HR for DFS 1.01, 95% CI 0.90-1.12). Moreover, NI was also declared for the subgroup treated with the CAPOX regimen (capecitabine plus oxaliplatin, ∼40% of patients), but the CAPOX choice was physician-based and not subject to randomization. Overall, the IDEA results indicate that three months of therapy might be adequate for most of Stage III tumors; however, a small subset of these patients still have high risk of recurrence and death with short treatment duration. Precise predictors of benefit need to be identified, nonetheless tumor-intrinsic factors, such as tumor stage, might currently be considered as useful tools to inform the decision-making process.

S-amlodipine plus chlorthalidone vs. S-amlodipine plus telmisartan in hypertensive patients unresponsive to amlodipine monotherapy: study protocol for a randomized controlled trial

BackgroundThe efficacy of a combination of a calcium channel blocker (CCB) plus chlorthalidone (diuretic) versus a CCB plus an angiotensin receptor blocker (ARB) in patients not responding to CCB monotherapy has not been evaluated previously. We plan to compare the efficacy and safety of S-amlodipine (CCB) plus chlorthalidone versus S-amlodipine plus telmisartan (ARB) combinations among hypertension patients unresponsive to amlodipine monotherapy.Methods/designThis study is a prospective, randomized, double-blind, multicenter, parallel, non-inferiority phase 4 study. Hypertension patients who have been treated with amlodipine (5 mg) or S-amlodipine (2.5 mg) monotherapy for ≥2 weeks and whose mean diastolic blood pressure (DBP) is greater than 90 mmHg will be randomized to either S-amlodipine (2.5 mg) plus chlorthalidone (25 mg) or S-amlodipine (2.5 mg) plus telmisartan (40 mg) therapy. The primary efficacy endpoint is mean sitting DBP change after 12 weeks of treatment. The study objective is to prove the non-inferiority of the former combination (test drug) as compared to the latter one (control) with a non-inferiority margin of 3 mmHg in mean DBP change. The secondary endpoints are 6-week DBP change, 6- and 12-week sitting systolic BP (SBP) change, and the attainment of the target BP (SBP < 140 mmHg or DBP < 90 mmHg). Urine albumin, albumin/creatinine ratio (ACR), pulse wave velocity, central BP, 24-h ambulatory BP monitoring, and body fluid composition analysis will be performed at each hospital’s discretion. The sample size was estimated as 170 in total with 1:1 randomization.DiscussionThis is the first study comparing the efficacy of a CCB plus chlorthalidone versus a CCB plus an ARB in patients who are not responding to CCB single therapy. The study result will help clinicians to choose between chlorthalidone and telmisartan in CCB-unresponsive patients.Trial registrationClinicalTrials.gov, NCT03226340. Registered on 2 December 2015.

PCN162 - Evaluation Of The Disease-Specific Items On The Eortc In Hepatocellular Carcinoma Patients Treated With Lenvatinib Or Sorafenib

To determine whether individual items on the EORTC-QLQ-C30 and hepatocellular carcinoma subscale are associated with statistically significant differences over the course of treatment for patients with unresectable hepatocellular carcinoma (uHCC). This was a multicenter, randomized, open-label, non-inferiority Phase 3 study comparing lenvatinib (LEN) to sorafenib (SOR) as first-line uHCC systemic treatments. 954 patients were randomized to LEN (N=478) or SOR (N=476). Analyses on the individual items of the EORTC QLQ-C30 and HCC18, were conducted using longitudinal generalized estimation equations (GEE) of the post-baseline, treated period assessments for these items. Forest plots of the odds ratios (OR) and associated confidence intervals (CI) from the GEE analyses were generated to characterize the likelihood of a 2-grade categorical deterioration (eg, deteriorate by 2 categories on the verbal response scale) on individual items for patients treated with LEN compared to SOR during the treatment period. The likelihood of patients experiencing a 2-grade deterioration over the course of the post-baseline treatment period was statistically equivalent for most EORTC-QLQ-C30 and HCC18 items (OR ~ 1.0) with the exception of pain in the shoulder, weight being too low, and reduced activity. Patients treated with SOR were 38% less likely to observe a 2-grade deterioration in shoulder pain (OR=0.7107, CI=0.5611-0.9003, p-value=0.0046). Patients treatment with LEN were 25% less likely to observe a 2-grade deterioration in weight being too low (OR=1.2502, CI=1.0014-1.5609, p-value=0.0485) and 27% less likely to observe a 2-grade deterioration in activity reduction (OR=1.2658, CI=1.0158-1.5774, p-value=0.0358). These data provide detailed information on the cumulative probability of categorical deterioration of individual items on the EORTC-QLQ-C30 and HCC18. These results show a similar trend with additional benefit of LEN in terms of anorexia or activity over the course of treatment, which are two key areas for patients especially the ability to perform activities.

PCN151 - Longitudinal Analysis Of Adjusted EQ-5D Utility Score At Baseline, Progression-Free Survival, And Progression For Lenvatinib Versus Sorafenib

To compare the impact of treatment on generic health related quality of life (QoL) factors for patients treated with lenvatinib (LEN) versus sorafenib (SOR) using the European Quality of Life questionnaire Five Dimension Scale (EQ-5D). This was a multicenter, randomized, open-label, non-inferiority Phase 3 study comparing LEN to SOR as first-line in patients with unresectable hepatocellular carcinoma systemic treatments. Longitudinal modelling of the EQ-5D Health Utility Index (HUI) was conducted to estimate the effect of treatment assignment (LEN versus SOR) on change from Baseline. Overall, a total of 954 patients (478 patients in the LEN treatment arm and 476 in the SOR treatment arm) were randomized. Baseline demographic and health information characteristics were not significantly different between treatment arms. In the EQ-5D, the mean change from Baseline visual analogue scale scores were observed to decrease with worsening modified Response Evaluation Criteria in Solid Tumors categories, with associated standardized effect size scores that decreased as disease severity increased. LEN and SOR arms had similar health utility scores at all baseline (Baseline: 0.804 versus 0.811, respectively). Previously presented post-Baseline progression-free survival visits were 19.7% lower for LEN (adjusted change from Baseline: -0.041 versus -0.050, respectively). A slight improvement in HUI scores (10.3%) were observed in LEN patients at disease progression based on the first post-Baseline progression visit (adjusted change from Baseline: -0.110 versus -0.122). Overall, these data illustrate that the LEN and SOR arms had similar health utility scores at all post-baseline, progression-free survival visits, with a slight improvement in HUI scores observed in LEN patients at disease progression. The change from Baseline to progression free survival and change from Baseline to post-progression was smaller for LEN compared to SOR.

Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, non-inferiority phase 3 trial

Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246. Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference -3·0%, 95% CI -8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths. Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia. Gilead Sciences Inc.

Abstract P3-01-02: Overview of the pathological results and treatment characteristics in the first 1000 patients randomized in the SERC trial: Axillary dissection versus no axillary dissection in patients with involved sentinel node

Abstract Background: Three randomized trials have concluded at non inferiority of omission of complementary axillary lymph node dissection (cALND) for patients with involved sentinel node (SN). However, we can outline strong limitations of these trials to validate this attitude with a high scientific level. We designed the SERC randomized trial to compare outcomes in patients with SN involvement treated with ALND or no further axillary treatment. The aim of this study was to analyze results of the first 1000 patients included. Patients and Methods: SERC trial is a multicenter non-inferiority phase 3 trial. Multivariate logistic regression analysis was used to identify independent factors associated with adjuvant chemotherapy administration and non-sentinel node (NSN) involvement. Results : Of the 963 patients included in the analysis set, 478 were randomized to receive cALND and 485 SLNB alone. All patient demographics and tumor characteristics were balanced between the two arms. SN ITC was present in 6.3% patients (57/903), micro metastases in 33.0% (298), macro metastases in 60.7% (548) and 289 (34.2%) were non eligible to Z0011 trial criteria. Whole breast or chest wall irradiation was delivered in 95.9% (896/934) of patients, adjuvant chemotherapy in 69.5% (644/926), endocrine therapy in 89.6% (673/751) and the proportions were similar in the two arms. The overall rate of positive NSN was 19% (84/442) for patients with cALND. Crude rates of positive NSN according to SN status were 4.5% for ITC (1/22), 9.5% for micro metastases (13/137), 23.9% for macro metastases (61/255) and were respectively 29.36% (64/218), 9.33% (7/75) and 7.94% (10/126) when chemotherapy was administered after cALND, before cALND and for patients without chemotherapy. Conclusion: The main objective of SERC trial is to demonstrate non inferiority of cALND omission. A strong interaction between timing of cALND and chemotherapy with positive NSN rate was observed. Citation Format: Houvenaeghel G, Cohen M, Raro P, De Troyer J, Tunon De Lara C, Guimbergues P, Gauthier T, Faure C, Vaini-Cowen V, Lantheaume S, Regis C, Darai E, Ceccato V, D'Halluin G, Del Piano F, Villet R, Jouve E, Beedassy B, Theret P, Gabelle P, Zinzindohoue C, Opinel P, Marsollier-Ferrer C, Dhainaut-Speyer C, Colombo P-E, Di Beo V, Lambaudie E, Tallet A, Boher J-M. Overview of the pathological results and treatment characteristics in the first 1000 patients randomized in the SERC trial: Axillary dissection versus no axillary dissection in patients with involved sentinel node [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-02.

(ICORG 05-03): prospective randomized non-inferiority phase III trial comparing two radiation schedules in malignant spinal cord compression (not proceeding with surgical decompression); the quality of life analysis

Background: The optimal primary external beam radiation therapy (EBRT) radiation schedule for malignant epidural spinal cord compression (MSCC) remains to be determined. The ICORG 05-03 trial assessed if a 10 Gy single fraction radiation schedule was not inferior to one with 20 Gray (Gy) in five daily fractions, in terms of functional motor outcome, for the treatment of MSCC in patients not proceeding with surgical decompression. This article reports on two of the secondary endpoints, Quality of life (QoL), assessed according to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0 (EORTC Data Center, Brussels, Belgium) and pain control assessed using a visual analog scale.Methods: A randomized, parallel group, multicenter phase III trial was conducted by Cancer Trials Ireland (formerly All-Ireland Cooperative Oncology Research Group, ICORG), across five hospital sites in Ireland and Northern Ireland. Patients were randomized to 10 Gy single fraction of EBRT or 20 Gy in five fractions in a 1:1 ratio. Patients with baseline and 5-week follow up QoL data are included in this analysis.Findings: From 2006 to 2014, 112 eligible patients were enrolled for whom 57 were evaluated for this secondary analysis. After adjusting for pre-intervention scores, there was no statistically significant difference in post-treatment Summary scores (excl. FI and QL), or pain scores between the two RT schedules at 5 weeks and 3 months following EBRT. There was a statistically significant relationship between the pretreatment and post-treatment Summary scores (p = .002) but not between the pre-treatment and post-treatment pain scores.Interpretation: Primary radiotherapy for the treatment of MSCC significantly improves QoL in patients not proceeding with surgical decompression. After adjusting for pre-intervention scores, there was no statistically significant difference between a 10 Gy single fraction radiation schedule and one with 20 Gy in five daily fractions on post-treatment QoL Summary scores. For most patients, an effective treatment with low burden would be desirable. A single fraction schedule should be considered for this group of patients.

Recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) versus alteplase (rt-PA) as fibrinolytic therapy for acute ST-segment elevation myocardial infarction (China TNK STEMI): protocol for a randomised, controlled, non-inferiority trial

AimTo evaluate the efficacy and safety of recombinant human TNK tissue-type plasminogen activator (rhTNK-tPA) in lowering major adverse cardiovascular and cerebrovascular events (MACCEs) in Chinese acute ST-segment elevation myocardial infarction...

Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study

Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1. The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402. Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1-17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications. The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women. ViiV Healthcare.

Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial

Studies in patients with rheumatoid arthritis have shown that the rituximab biosimilar CT-P10 (Celltrion, Incheon, South Korea) has equivalent efficacy and pharmacokinetics to rituximab. In this phase 3 study, we aimed to assess the non-inferior efficacy and pharmacokinetic equivalence of CT-P10 compared with rituximab, when used in combination with cyclophosphamide, vincristine, and prednisone (CVP) in patients with newly diagnosed advanced-stage follicular lymphoma. In this ongoing, randomised, double-blind, parallel-group, active-controlled study, patients aged 18 years or older with Ann Arbor stage III-IV follicular lymphoma were assigned 1:1 to CVP plus intravenous infusions of 375 mg/m2 CT-P10 or rituximab on day 1 of eight 21-day cycles. Randomisation was done by the investigators using an interactive web or voice response system and a computer-generated randomisation schedule, prepared by a clinical research organisation. Randomisation was balanced using permuted blocks and was stratified by country, gender, and Follicular Lymphoma International Prognostic Index score (0-2 vs 3-5). Study teams from the sponsor and clinical research organisation, investigators, and patients were masked to treatment assignment. The study was divided into two parts: part 1 assessing equivalence of pharmacokinetics (in the pharmacokinetics subset), and part 2 assessing efficacy in all randomised patients (patients from the pharmacokinetics subset plus additional patients enrolled in part 2). Equivalence of pharmacokinetics was shown if the 90% CIs for the geometric mean ratio of CT-P10 to rituximab in AUCτ and CmaxSS were within the bounds of the equivalence margin of 80% and 125%. Non-inferiority of response was shown if the one-sided 97·5% CI lay on the positive side of the -7% margin, using a one-sided test done at the 2·5% significance level. The primary efficacy endpoint was the proportion of patients who had an overall response over eight cycles and was assessed in the efficacy population (all randomised patients). The primary pharmacokinetic endpoints were area under the serum concentration-time curve at steady state (AUCτ) and maximum serum concentration at steady state (CmaxSS) at cycle 4, assessed in the pharmokinetic population. This trial is registered with ClinicalTrials.gov, number NCT02162771. Between July 28, 2014, and Dec 29, 2015, 140 patients were enrolled. Here we report data for the eight-cycle induction period, up to week 24. The proportion of patients with an overall response in the efficacy population was 64 (97·0%) of 66 patients in the CT-P10 treatment group and 63 (92·6%) of 68 patients in the rituximab treatment group (4·3%; one-sided 97·5% CI -4·25), which lay on the positive side of the predefined non-inferiority margin. The ratio of geometric least squares means (CT-P10/rituximab) was 102·25% (90% CI 94·05-111·17) for AUCτ and 100·67% (93·84-108·00) for CmaxSS, with all CIs within the bioequivalence margin of 80-125%. Treatment-emergent adverse events were reported for 58 (83%) of 70 patients in the CT-P10 treatment group and 56 (80%) of 70 in the rituximab treatment group. The most common grade 3 or 4 treatment-emergent adverse event in each treatment group was neutropenia (grade 3, 15 [21%] of 70 patients in the CT-P10 group and seven [10%] of 70 patients in the rituximab group). The proportion of patients who experienced at least one treatment-emergent serious adverse event was 16 (23%) of 70 patients in the CT-P10 group and nine (13%) of 70 patients in the rituximab group. In this study, we show that CT-P10 exhibits non-inferior efficacy and pharmacokinetic equivalence to rituximab. The safety profile of CT-P10 was comparable to that of rituximab. CT-P10 might represent a new therapeutic option for advanced-stage follicular lymphoma. Celltrion, Inc.

SCORAD III: Randomized noninferiority phase III trial of single-dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC).

LBA10004 Background: SCC is a common complication of metastatic cancer. Most pts receive RT to improve neurological function and mobility and to relieve pain. There is no standard schedule (RT ranges from single dose 8Gy to 40Gy in 20 fractions). SCORAD III was conducted to show whether a single fraction is as effective as multifraction RT without compromising patient outcomes. Methods: Pts from 43 UK and 4 Australian sites were randomized (1:1) to receive external beam spinal canal RT as a single dose of 8Gy or 20Gy in 5 fractions; stratified by RT center, ambulatory status (AS), site of primary, and presence or absence of nonskeletal metastases. Eligible pts had spinal cord or cauda equina (C1-S2) compression confirmed by MRI/CT scan, treatable within a single radiation field, life expectancy &gt;8 weeks (wks), no previous RT to the same area. Primary endpoint was AS at wk 8: graded 1 (full function) to 4 (no/flicker motor power). The noninferiority margin was 11% for comparing the proportion of patients with AS 1 or 2 at wk 8 (whether maintained from baseline or improved from AS 3-4). Results: 688 pts were randomized Feb 2008 to Apr 2016 (n=345 single dose, n=343 multifraction). 73% were male; median age 70 years; ambulatory with/without walking aids 66%; 44% prostate, 18% lung, 11% breast, 11% gastrointestinal. Baseline characteristics were balanced. 69.5% (114/164 pts evaluable at wk 8) single dose vs. 73.3% (129/176) multifraction had AS 1-2 at wk 8 (risk difference: -3.78%, 90%CI -11.85 to 4.28). Importantly, overall survival (OS) was very similar: median OS 12.4 wks single dose vs. 13.7 multifraction, (hazard ratio 1.02 [95%CI 0.86-1.21], p=0.81). Proportion of pts with adverse events was similar for grade 3-4 (20.6% single dose vs. 20.4% multifraction), but grade 1-2 events were lower with single dose (51.0% vs. 56.9%). Conclusions: Using a single dose of 8Gy in pts with metastatic SCC was as effective as multiple fractions for AS at 8 wks and OS. We now recommend using single dose RT in this setting, with the major benefit of requiring only a single instead of multiple hospital visits, important when considering the short survival in these pts. Clinical trial information: 97108008.

Targeted simplification versus antipseudomonal broad-spectrum beta-lactams in patients with bloodstream infections due to Enterobacteriaceae (SIMPLIFY): a study protocol for a multicentre, open-label, phase III randomised, controlled, non-inferiority clinical trial

IntroductionWithin the context of antimicrobial stewardship programmes, de-escalation of antimicrobial therapy is one of the proposed strategies for reducing the unnecessary use of broad-spectrum antibiotics (BSA). The empirical treatment of...

SCORAD III: Randomized noninferiority phase III trial of single-dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC).

LBA10004 The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies.

Oral pharmacotherapies to treat overactive bladder (OAB) are used less in men despite a similar prevalence of storage symptoms as women. The efficacy and safety of once-daily mirabegron 50 mg was evaluated in male OAB patients from five phase III studies that included placebo or antimuscarinic (tolterodine ER 4 mg or solifenacin 5 mg) as a comparator. Three pooled 12-week placebo-controlled studies (mirabegron 50 mg versus placebo) and one 12-week non-inferiority phase IIIb study (BEYOND; mirabegron 50 mg versus solifenacin 5 mg) were used for efficacy (daily micturition frequency, urgency and incontinence episodes) and safety analyses. An additional 52-week active-controlled phase III safety study (mirabegron 50 mg versus tolterodine ER 4 mg) was included in the safety analysis. Male patients aged ⩾18 years with OAB for ⩾3 months were included in the analyses. Patients may also have a history of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)/benign prostatic enlargement (BPE) or concomitant use of α1-blockers. In the pooled studies, mirabegron 50 mg demonstrated superiority versus placebo (treatment difference: -0.37 [95% confidence interval (CI): -0.74, -0.01]) for reducing micturition frequency; improvements in urgency and incontinence were not significantly different between mirabegron 50 mg and placebo. In BEYOND, mirabegron 50 mg was comparable with solifenacin 5 mg for reducing micturition frequency, urgency, and incontinence episodes. Mirabegron was well tolerated at 12 and 52 weeks and overall treatment-emergent adverse events (AEs) were similar to those with placebo. In a male OAB population with or without LUTS associated with BPH/BPE, mirabegron 50 mg provided similar improvements in urgency, frequency, and incontinence as solifenacin 5 mg, and is a well-tolerated alternative to antimuscarinics. In the three pooled 12-week studies, significant differences were not seen for urgency and incontinence versus placebo, although mirabegron 50 mg did demonstrate significant improvements versus placebo for frequency.