Non-inferior Margin Research Articles

Efficacy and safety of paclitaxel liposome versus paclitaxel in combination with carboplatin in the first-line chemotherapy for ovarian cancer: a multicenter, open-label, non-inferiority, randomized controlled trial

BackgroundThe paclitaxel liposome formulation, encapsulating paclitaxel within a phospholipid bilayer, addresses the insolubility of traditional paclitaxel formulations, thereby reducing toxicity without compromising its antitumor efficacy. MethodsThis multicenter, open-label, non-inferiority randomized controlled trial (ChiCTR2000038555) evaluates the efficacy and safety of paclitaxel liposome in comparison to the standard regimen of paclitaxel combined with carboplatin (PLC vs. PC) as first-line therapy in patients with epithelial ovarian cancer. ResultsAn analysis of median progression-free survival (PFS) revealed non-inferior outcomes between 263 patients in the PLC group and 260 patients in the PC group (32.3 vs. 29.9 months, hazard ratio [HR], 0.89 [95% CI, 0.64−1.25]), using a non-inferior margin of 1.3. Although the overall incidence of treatment-related adverse events was comparable between groups, the PLC group experienced significantly fewer non-hematologic toxicities than those treated with the PC regimen. ConclusionThe findings affirm the non-inferiority of paclitaxel liposome compared to the combination of paclitaxel and carboplatin regarding therapeutic efficacy, with an enhanced safety profile marked by reduced non-hematologic toxicities.

HYPOCx-iRex (TCTR20210812003) A Phase II RCT: 44 Gy/20F VS 45 Gy/25F CCRT in Cervical Cancer: Six-month Post-RT Update

Hypofractionation for definitive concurrent chemoradiation (CCRT) in locally advanced cervical cancer (LACC) may increase RT efficacy but scarce in data. Early results of HYPOCx-iRex trial at 3-mo follow-up (F/U) time showed a non-statistically significant small rise but auto-resolved acute GI toxicity of HYPO 44 Gy/20F arm compared to CVRT 45 Gy/25F arm, yet significantly retracted overall treatment time and time to brachytherapy without compromised GTV reduction or tumor response. This prespecified interim analysis at 6-mo post-RT of the first 20 patients was intended to prove non-inferior late toxicity, oncologic outcome and pattern of failure of HYPO in addition to previous ESTRO2023 abstract. Patients with LACC were enrolled since July 2021. ≥3 Pelvic LN or at/above common iliac were excluded to omit paraaortic RT. Open-label randomization was performed for IMRT/VMAT to HYPO for 44 Gy/20F to whole pelvis and 53 Gy/20F SIB to gross LN in five-day-a-week fractions, and for CVRT 45 and 55 Gy/25F, with concurrent weekly cisplatin 40 mg/m2. Target contour and planning dose of EBRT and IGABT were adapted and biologically converted from EMBRACE-II. Indirect ratio of excess dose volume (iRex; DOI: 10.5114/jcb.2020.100377) as a complimentary low-dose conformity index to D2cc-based IGABT was explored, but analysis was out of this abstract scope. Non-inferiority margin of 9% 5-yr GI toxicity difference of HYPO and CVRT with one-sided α = 0.5 and 1-β = 0.8 yielded 40-patient sample size for toxicity screening. Adopting 9% margin, analysis at 6-mo post-RT of the first 20 patients were done with descriptive and survival analysis. Twenty-nine patients with median F/U time from start of RT of 8 months were included. Non-significant difference of IGABT dose was seen. Median post-RT time were 7 months with non-significant difference in 6-mo crude, late and persistent (LAPER), or cumulative GI and GU toxicity. Unfortunately, difference of -0.07 [95% CI -0.47 to +0.32] cumulative GI toxicity exceeded margin of +0.09, but the p value is greater than 0.5 (cut-off for go or no go for phase III study). No significant oncologic outcome nor pattern of failure difference were shown. HYPO 44 Gy/20F showed trend of non-significant difference in 6-mo toxicity nor oncologic outcome. The unmet non-inferior margin should be re-evaluated at trial completion for further implementation.

Transfascial Fixation vs No Fixation for Open Retromuscular Ventral Hernia Repairs

Transfascial (TF) mesh fixation in open retromuscular ventral hernia repair (RVHR) has been advocated to reduce hernia recurrence. However, TF sutures may cause increased pain, and, to date, the purported advantages have never been objectively measured. To determine whether abandonment of TF mesh fixation would result in a noninferior hernia recurrence rate at 1 year compared with TF mesh fixation in open RVHR. In this prospective, registry-based, double-blinded, noninferiority, parallel-group, randomized clinical trial, a total of 325 patients with a ventral hernia defect width of 20 cm or less with fascial closure were enrolled at a single center from November 29, 2019, to September 24, 2021. Follow-up was completed December 18, 2022. Eligible patients were randomized to mesh fixation with percutaneous TF sutures or no mesh fixation with sham incisions. The primary outcome was to determine whether no TF suture fixation was noninferior to TF suture fixation for open RVHR with regard to recurrence at 1 year. A 10% noninferior margin was set. The secondary outcomes were postoperative pain and quality of life. A total of 325 adults (185 women [56.9%]; median age, 59 [IQR, 50-67] years) with similar baseline characteristics were randomized; 269 patients (82.8%) were followed up at 1 year. Median hernia width was similar in the TF fixation and no fixation groups (15.0 [IQR, 12.0-17.0] cm for both). Hernia recurrence rates at 1 year were similar between the groups (TF fixation, 12 of 162 [7.4%]; no fixation, 15 of 163 [9.2%]; P = .70). Recurrence-adjusted risk difference was found to be -0.02 (95% CI, -0.07 to 0.04). There were no differences in immediate postoperative pain or quality of life. The absence of TF suture fixation was noninferior to TF suture fixation for open RVHR with synthetic mesh. Transfascial fixation for open RVRH can be safely abandoned in this population. ClinicalTrials.gov Identifier: NCT03938688.

Laparo-endoscopic single-site versus conventional laparoscopic surgery for early-stage endometrial cancer: A randomized controlled non-inferiority trial

ObjectiveTo evaluate the feasibility and safety of laparo-endoscopic single-site surgery (LESS) compared with conventional laparoscopic surgery (CLS) for early-stage endometrial cancer. MethodsPatients with clinical stage IA, IB, grade 1–3 endometrial cancer were randomly assigned to undergo LESS or CLS. The primary endpoint was the non-inferiority of LESS to CLS in terms of operation time and the number of resected pelvic lymph nodes. We set the non-inferior margin of the operation time as within 15% (24 min) and the number of resected pelvic lymph nodes as within 20% (5.2 lymph nodes). ResultsThere was no significant difference between the LESS group (n = 53) and the CLS group (n = 54) in terms of age, weight, body mass index, parity, menopausal status, history of abdominal surgery, and preoperative CA-125 levels. The total operation time was comparable between the two groups. On average, 4.6 fewer pelvic lymph nodes were retrieved in the LESS group, which was within the non-inferiority margin. There were no significant differences in the incidence of intra- and postoperative complications, estimated blood loss, and postoperative hospital stay between the two groups. After a median follow-up time of 34 months (range, 2–242), the progression-free survival rates were 96.2% and 98.1% (P = 0.55) in the LESS group and the CLS group, and the overall survival rates were 98.1% and 100.0% (P = 0.31), respectively. ConclusionLESS surgical staging was non-inferior to CLS and had acceptable feasibility, safety, and efficacy for the surgical management of early-stage endometrial cancer.Trial registration: Clinicaltrial.gov identifier number: NCT01679522

Transcutaneous Electrical Cranial-Auricular Acupoint Stimulation vs. Escitalopram for Patients With Mild-to-Moderate Depression (TECAS): Study Design for a Randomized Controlled, Non-inferiority Trial.

BackgroundPrevious studies in animals and humans indicated that transcutaneous vagus nerve stimulation (tVNS) and transcutaneous electrical acupoint stimulation (TEAS) on trigeminal nerve-innervated forehead acupoints can relief the symptoms of depression. However, due to the limited investigations on these two interventions, more research are needed to confirm their efficacy in depression. To improve the efficacy of the single treatment, we combined two treatments and created a novel non-invasive stimulation, transcutaneous electrical cranial-auricular acupoint stimulation (TECAS). To assess the efficacy and safety of TECAS, we compare it with a selective serotonin reuptake inhibitor (SSRI), escitalopram, for the treatment of depression.Methods/DesignThis is a multi-center, non-inferiority, randomized controlled trial that will involve 470 patients with mild to moderate depression. Patients will be randomly assigned to either the TECAS group or the escitalopram group in a 1:1 ratio. The TEAS group will receive two sessions of treatments per day for 8 consecutive weeks, and the escitalopram group will receive 8 weeks of oral escitalopram tablets prescribed by clinical psychiatrists as appropriate for their condition. The primary outcome is the clinical response as determined by Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 8, with −10% as the non-inferior margin. The secondary outcomes include the response rate determined by 17-item Hamilton Depression Rating Scale (HAMD-17), remission rate, changes from baseline in the scores on the MADRS, the HAMD-17, the Hamilton Anxiety Rating Scale (HAMA), the Pittsburgh Sleep Quality Index (PSQI), and the Short Form 36 Health Survey (SF-36).DiscussionThis will be the first randomized controlled trial to compare the efficacy of TECAS with escitalopram for depression. If effective, this novel intervention could have significant clinical and research implications for patients with depression.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT03909217].

Randomized phase II study of nalicap (nal-IRI/capecitabine) compared to NAPOLI (nal-IRI/5-FU/LV) in gemcitabine-pretreated advanced pancreatic cancer: Trial-in-progress.

TPS621 Background: Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and folinic acid (LV), called the NAPOLI regimen, improves survival in advanced pancreatic cancer patients who failed gemcitabine-based chemotherapy (Wang-Gillam A et al. 2016). Capecitabine is an oral anti-cancer agent as the prodrug of 5-FU. Capecitabine has proven its efficacy in gastrointestinal cancers like stomach cancer, colon cancer, or pancreatic cancer. Replacing continuous 5-FU infusions with oral capecitabine with equivalent efficacy has been tested and is now widely used. However, in pancreatic cancer, replacing continuous infusion of 5-FU with an oral drug has not yet been tested. Therefore, this trial is being conducted with the aim of improving patient convenience while maintaining efficacy, when the continuous infusion of 5-FU/LV in NAPOLI (nal-IRI/5-FU/LV) regimen are replaced with oral capecitabine. This study is a two-arm, open-label, multicenter, randomized phase 2 trial to assess whether capecitabine plus nal-IRI combination treatment (NaliCap) is non-inferior to NAPOLI regimen in gemcitabine-pretreated patients with advanced pancreatic cancer. Methods: Eligible patients have histologically confirmed pancreatic adenocarcinoma who have failed to gemcitabine-based chemotherapy. This trial is composed of two parts: safety lead-in-part and randomization part. NaliCap regimen consists of administration of capecitabine twice daily for day 1-14 and intravenous administration of nal-IRI for day 1 every 3weeks. To figure out recommended phase 2 dose of the NaliCap combination regimen, the safety lead-in-part is being conducted as a 3+3 design. In the randomization part, patients will be assigned to NAPOLI or NaliCap in a 1:1 ratio. The planned enrollment is 184 patients in the randomization part. Patients allocated to the NaliCap group will receive recommended phase 2 dose of NaliCap determined through the safety lead-in-part. Patients allocated with the NAPOLI group will receive nal-IRI 70mg/m2 intravenously day 1, LV 400mg/m2 IV day 1, and continuous 5-FU 2400mg/m2 infusion over 48hours every 2weeks. Response assessments are performed every 6 weeks using the RECIST criteria version 1.1 (every 2 cycles in the NaliCap group and every 3 cycles in the NAPOLI group). The primary endpoint is progression-free survival, with a non-inferior margin of the hazard ratio of 1.4. Key secondary endpoints are overall response rate, disease control rate, overall survival, safety, and quality of life. This study is prospectively registered at ClinicalTrials.gov, NCT04371224. Clinical trial information: NCT04371224.

Image quality in liver CT: low-dose deep learning vs standard-dose model-based iterative reconstructions

To compare the overall image quality and detectability of significant (malignant and pre-malignant) liver lesions of low-dose liver CT (LDCT, 33.3% dose) using deep learning denoising (DLD) to standard-dose CT (SDCT, 100% dose) using model-based iterative reconstruction (MBIR). In this retrospective study, CT images of 80 patients with hepatic focal lesions were included. For noninferiority analysis of overall image quality, a margin of - 0.5 points (scored in a 5-point scale) for the difference between scan protocols was pre-defined. Other quantitative or qualitative image quality assessments were performed. Additionally, detectability of significant liver lesions was compared, with 64 pairs of CT, using the jackknife alternative free-response ROC analysis, with noninferior margin defined by the lower limit of 95% confidence interval (CI) of the difference of figure-of-merit less than - 0.1. The mean overall image quality scores with LDCT and SDCT were 3.77 ± 0.38 and 3.94 ± 0.34, respectively, demonstrating a difference of - 0.17 (95% CI: - 0.21 to - 0.12), which did not cross the predefined noninferiority margin of - 0.5. Furthermore, LDCT showed significantly superior quantitative results of liver lesion contrast to noise ratio (p < 0.05). However, although LDCT scored higher than the average score in qualitative image quality assessments, they were significantly lower than those of SDCT (p < 0.05). Figure-of-merit for lesion detection was 0.859 for LDCT and 0.878 for SDCT, showing noninferiority (difference: - 0.019, 95% CI: - 0.058 to 0.021). LDCT using DLD with 67% radiation dose reduction showed non-inferior overall image quality and lesion detectability, compared to SDCT. • Low-dose liver CT using deep learning denoising (DLD), at 67% dose reduction, provided non-inferior overall image quality compared to standard-dose CT using model-based iterative reconstruction (MBIR). • Low-dose CT using DLD showed significantly less noise and higher CNR lesion to liver than standard-dose CT using MBIR and demonstrated at least average image quality score among all readers, albeit with lower scores than standard-dose CT using MBIR. • Low-dose liver CT showed noninferior detectability for malignant and pre-malignant liver lesions, compared to standard-dose CT.

Pulmonary vein isolation alone vs. more extensive ablation with defragmentation and linear ablation of persistent atrial fibrillation: the EARNEST-PVI trial.

Previous studies could not demonstrate any benefit of more intensive ablation in addition to pulmonary vein isolation (PVI) including complex fractionated atrial electrogram (CFAE) and linear ablation for recurrence in the initial catheter ablation of persistent atrial fibrillation (AF). This study aimed to establish the non-inferiority of PVI alone to PVI plus these additional ablation strategies. Patients with persistent AF who underwent an initial catheter ablation (n = 512, long-standing persistent AF; 128 cases) were randomly assigned in a 1:1 ratio to either PVI alone (PVI-alone group) or PVI plus CFAE and/or linear ablation (PVI-plus group). After excluding 15 cases who did not receive procedures, we analysed 249 and 248 patients, respectively. The primary endpoint was recurrence of AF, atrial flutter, and/or atrial tachycardia, and the non-inferior margin was set at a hazard ratio of 1.43. In the PVI-plus group, 85.1% of patients had linear ablation and 15.3% CFAE ablation. After 12 months, freedom from the primary endpoint occurred in 71.3% of patients in the PVI-alone group and in 78.3% in the PVI-plus group [hazard ratio = 1.56 (95% confidence interval: 1.10-2.24), non-inferior P = 0.3062]. The procedure-related complication rates were 2.0% in the PVI-alone group and 3.6% in the PVI-plus group (P = 0.199). This randomized trial did not establish the non-inferiority of PVI alone to PVI plus linear ablation or CFAE ablation in patients with persistent AF, but implied that the PVI plus strategy was promising to improve the clinical efficacy (NCT03514693).

High-flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease patients after extubation: a multicenter, randomized controlled trial

BackgroundHigh-flow nasal cannula (HFNC) oxygen therapy is being increasingly used to prevent post-extubation hypoxemic respiratory failure and reintubation. However, evidence to support the use of HFNC in chronic obstructive pulmonary disease (COPD) patients with hypercapnic respiratory failure after extubation is limited. This study was conducted to test if HFNC is non-inferior to non-invasive ventilation (NIV) in preventing post-extubation treatment failure in COPD patients previously intubated for hypercapnic respiratory failure.MethodsCOPD patients with hypercapnic respiratory failure who were already receiving invasive ventilation were randomized to HFNC or NIV at extubation at two large tertiary academic teaching hospitals. The primary endpoint was treatment failure, defined as either resumption of invasive ventilation or switching to the other study treatment modality (NIV for patients in the NFNC group or vice versa).ResultsNinety-six patients were randomly assigned to the HFNC group or NIV group. After secondary exclusion, 44 patients in the HFNC group and 42 patients in the NIV group were included in the analysis. The treatment failure rate in the HFNC group was 22.7% and 28.6% in the NIV group—risk difference of − 5.8% (95% CI, − 23.8–12.4%, p = 0.535), which was significantly lower than the non-inferior margin of 9%. Analysis of the causes of treatment failure showed that treatment intolerance in the HFNC group was significantly lower than that in the NIV group, with a risk difference of − 50.0% (95% CI, − 74.6 to − 12.9%, p = 0.015). One hour after extubation, the mean respiratory rates of both groups were faster than their baseline levels before extubation (p < 0.050). Twenty-four hours after extubation, the respiratory rate of the HFNC group had returned to baseline, but the NIV group was still higher than the baseline. Forty-eight hours after extubation, the respiratory rates of both groups were not significantly different from the baseline. The average number of daily airway care interventions in the NIV group was 7 (5–9.3), which was significantly higher than 6 (4–7) times in the HFNC group (p = 0.006). The comfort score and incidence of nasal and facial skin breakdown of the HFNC group was also significantly better than that of the NIV group [7 (6–8) vs 5 (4–7), P < 0.001] and [0 vs 9.6%, p = 0.027], respectively.ConclusionAmong COPD patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of HFNC after extubation did not result in increased rates of treatment failure compared with NIV. HFNC also had better tolerance and comfort than NIV.Trial registrationchictr.org (ChiCTR1800018530). Registered on 22 September 2018, http://www.chictr.org.cn/usercenter.aspx

Electrospun P(LLA-CL) Nanoscale Fibrinogen Patch vs Porcine Small Intestine Submucosa Graft Repair of Inguinal Hernia in Adults: A Randomized, Single-Blind, Controlled, Multicenter, Noninferiority Trial

The aim of this study was to compare primary efficacy indicators of a low-cost, electrospun, nanoscale P(LLA-CL)/fibrinogen patch with a porcine small intestine submucosa patch for hernia repair. A randomized, single-blind, controlled multicenter trial was performed in 3 hospitals in Shanghai. Eligible patients (20 to 75 years old) with primary unilateral, reducible groin hernias were randomly assigned (1:1) to electrospun nanoscale P(LLA-CL)/fibrinogen patch (experimental group) or porcine small intestine submucosa (control group) patch groups. Patients were treated with the Lichtenstein technique, and the primary endpoint was hernia recurrence at 33 months after surgery. The secondary endpoints were postoperative complications including groin pain and operative site infections. Between July 2014 and February 2016, 172 patients were assigned to experimental (n= 86) and control (n= 86) groups. At 6-month follow-up, postoperative complications occurred in 5 patients (5 of 86, 5.81%) and 2 (2 of 86, 2.35%) patients in the control and experimental groups, respectively (p < 0.05). At 33-month follow-up, recurrence was observed in 2 patients (2 of 79, 2.53%) in the control group vs none in the experimental group (0 of 78) (the 95% CI difference between the experimental and control groups was -0.93% to 6.00% and within the preset noninferior margin of Δ10%). No significant differences were found in the degree of chronic pain and complications 33 months after surgery between the 2 groups. Because the recurrence rates and postoperative complications after 33 months were not inferior in the experimental group, we believe that the P(LLA-CL)/fibrinogen patch, as a low cost alternative, has prospects for widespread clinical use.

Twelve-month angiographic and clinical outcomes of the XINSORB bioresorbable sirolimus-eluting scaffold and a metallic stent in patients with coronary artery disease

BackgroundRecent studies showed bioresorbable scaffold (BRS) increased risks of late target lesion failure (TLF) and thrombosis. XINSORB scaffold is a poly-L-lactic acid based BRS. MethodsThe study included randomization and registry parts. Eligible patients with one or two de novo lesions were randomly 1:1 assigned to XINSORB scaffold and sirolimus-eluting stent (SES) in randomization part. These patients were clinically and angiographically assessed. In registry part, patients were treated with XINSORB scaffold only and were clinically assessed. The primary endpoint was in-segment late luminal loss (LLL) at 12-month in randomization part. The secondary endpoint was 12-month TLF in all XINSORB-treated patients. ResultsTotal 395 and 798 patients were enrolled in randomization and registry part, respectively. Device success was 98.0% (1069/1091) in all XINSORB-treated and 100% (221/221) in SES-treated lesions. The primary endpoint of in-segment LLL at 12-month was 0.19 ± 0.32 mm in XINSORB and 0.31 ± 0.41 mm in SES (P = 0.003), which met the noninferior margin of 0.195 mm (95% CI: −0.20, −0.04, P ≪ 0.0001). No difference was found in TLF between two devices. In all XINSORB-treated patients, 12-month TLF was 0.8% (8/998), which also met the noninferior margin of 9.0% (95% CI: 0.3%, 1.4%, P ≪ 0.0001). Only one device thrombosis was recorded in all XINSORB-treated patients while none in SES. ConclusionsIn the multicenter clinical trial, XINSORB BRS was noninferior to sirolimus-eluting stent for the primary endpoint of in-segment LLL at 12-month in patients with simple and moderate complex de novo coronary lesions. TLF at 12-month was low and comparable.

55-OR: Oral Semaglutide vs. Liraglutide and Placebo in T2D: PIONEER 4

Patients (pts) with T2D uncontrolled on metformin ± SGLT2i were randomized to oral semaglutide (sema) 14 mg once daily (N=285), liraglutide (lira) 1.8 mg (N=284) or placebo (pbo, N=142) in a phase 3a, 52-week, double-blind, double-dummy trial (NCT02863419). Endpoints: Change (baseline to week 26) in HbA1c (primary) and body weight (BW, confirmatory secondary). Two estimands addressed two efficacy-related questions: Treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized pts. Treatment policy estimand: Oral sema was non-inferior (margin 0.4%) to lira and superior to pbo in reducing HbA1c, and superior to both in reducing BW at week 26 (Table). Differences in both HbA1c and BW were significant at week 52. Trial product estimand: Oral sema gave significant reductions in HbA1c and BW vs. lira and pbo at weeks 26 and 52. Oral sema had comparable tolerability to lira; 11% (oral sema) vs. 9% (lira) and 4% (pbo) prematurely discontinued trial product due to adverse events (primarily gastrointestinal; 5% [oral sema] vs. 3% [lira] discontinued due to nausea). In conclusion, oral sema was well tolerated in pts with T2D on metformin ± SGLT2i, was non-inferior vs. lira and superior vs. pbo in reducing HbA1c, and was superior in reducing BW vs. both lira and pbo. The reduction in HbA1c was significantly better vs. lira when evaluated by the trial product estimand. Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research &amp; Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. A. Amod: Advisory Panel; Self; Aspen Pharmacare, AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis, Servier. S.T. Hoff: Employee; Self; Novo Nordisk A/S. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. I. Lingvay: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation. Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi, TARGET PharmaSolutions, Valeritas, Inc. Research Support; Self; Merck &amp; Co., Inc., Mylan, Novo Nordisk Inc., Pfizer Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sun Pharma. K. Pedersen: Employee; Self; Novo Nordisk A/S. T. Saugstrup: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Zealand Pharma A/S. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. Funding Novo Nordisk A/S

Randomized clinical trial of famciclovir or acyclovir for the treatment of herpes zoster in adults

BackgroundThis study investigated the safety and efficacy of famciclovir compared to acyclovir in patients with herpes zoster, to determine whether the two regimens are equally effective for the treatment of patients with uncomplicated herpes zoster over a period of 7days. MethodsPatients were randomly assigned to receive either famciclovir 500mg (one tablet) three times daily or acyclovir 800mg (two capsules) five times daily for 7 days. The primary endpoint was defined as the time to full crusting of herpes zoster lesions. Secondary endpoints were the proportion of patients who achieved complete cure and the change in score of signs/symptoms (pain, vesicular lesions, loss of sensitivity, burning pain, and pruritus) according to the patient diary. This study has been registered at ClinicalTrials.gov (NCT01327144). ResultsOne hundred and seventy-four patients were enrolled and randomized; 151 of these patients completed treatment (n=75 famciclovir, n=76 acyclovir). A similar proportion of patients who received acyclovir (94.74%) and famciclovir (94.67%) achieved complete cure. The mean time to full crusting of herpes zoster lesions was 15.033days in the acyclovir group and 14.840days in the famciclovir group (log-rank p-value=0.820). The most common adverse events in the pooled groups were headache, diarrhea, nausea, back pain, cold, and drowsiness, but none of these was deemed to be clinically important. ConclusionsBoth interventions obtained high rates of cure and had a similar time to full crusting of lesions. Analysis of the primary efficacy endpoint proved that famciclovir is non-inferior to acyclovir, as the confidence interval for the difference in efficacy did not violate the non-inferior margin. Therefore, the results are not different enough to be clinically relevant.

Percutaneous Interspinous Spacer vs Decompression in Patients with Neurogenic Claudication: An Alternative in Selected Patients?

BACKGROUNDStandalone interspinous process devices (IPDs) to treat degenerative lumbar spinal stenosis with neurogenic intermittent claudication (NIC) have shown ambiguous results in the literature.OBJECTIVETo show that a minimally invasive percutaneous IPD is safe and noninferior to standalone decompressive surgery (SDS) for patients with degenerative lumbar spinal stenosis with NIC.METHODSA multicenter, international, randomized, controlled trial (RCT) was con- ducted. One hundred sixty-three patients, enrolled at 19 sites, were randomized 1:1 to treatment with IPD or SDS and were followed for 24 mo.RESULTSThere was significant improvement in Zurich Claudication Questionnaire physical function, as mean percentage change from baseline, for both the IPD and the SDS groups at 12 mo (primary endpoint) and 24 mo (−32.3 ± 32.1, −37.5 ± 22.8; and −37.9 ± 21.7%, −35.2 ± 22.8, both P < .001). IPD treatment was not significantly noninferior (margin: 10%) to SDS treatment at 12 mo (P = .172) but was significantly noninferior at 24 mo (P = .005). Symptom severity, patient satisfaction, visual analog scale leg pain, and SF-36 improved in both groups over time. IPD showed lower mean surgical time and mean blood loss (24 ± 11 min and 6 ± 11 mL) compared to SDS (70 ± 39 min and 189 ± 148 mL, both P < .001). Reoperations at index level occurred in 18.2% of the patients in the IPD group and in 9.3% in the SDS group.CONCLUSIONConfirming 3 recent RCTs, we could show that IPD as well as open decompression achieve similar results in relieving symptoms of NIC in highly selected patients. However, despite some advantages in secondary outcomes, a higher reoperation rate for IPD is confirmed.

Selective Suprascapular and Axillary Nerve Block Versus Interscalene Plexus Block for Pain Control After Arthroscopic Shoulder Surgery

This randomized trial aimed to assess if a combined suprascapular-axillary nerve block (SSB) is noninferior (margin = 1.3 on a 0- to 10-point scale) to interscalene block (ISB) in treating pain after arthroscopic shoulder surgery. Secondary end points included opioid consumption, dyspnea, discomfort associated with muscle weakness, and patient satisfaction. One hundred patients undergoing arthroscopic shoulder surgery were randomized to receive ultrasound-guided ISB (n = 50) or SSB (n = 50). Pain intensity at rest, dyspnea, and discomfort were recorded upon arrival in the recovery room, discharge to the ward, and at 4, 8, and 24 hours after surgery. Piritramide consumption was recorded for the first 24 hours. Patient satisfaction was assessed on the second postoperative day. During the first 4 hours after surgery, the difference in mean pain score between SSB and ISB was higher than 2.5 (±0.8). The difference gradually decreased to 1.1 (±1.0) at 8 hours before resulting in noninferiority during the night and at 24 hours. Piritramide consumption was significantly higher in the SSB group in the first 8 hours. The incidence of dyspnea and discomfort was higher after ISB. Treatment satisfaction was similar in both groups. Suprascapular-axillary nerve block is inferior to ISB in terms of analgesia and opioid requirement in the immediate period after arthroscopic shoulder surgery but is associated with a lower incidence of dyspnea and discomfort. The difference in pain and opioid consumption gradually decreases as the blocks wear off in order to reach similar pain scores during the first postoperative night and at 24 hours. This study was registered at ClinicalTrials.gov, identifier NCT02415088.

Comparison of Glycemic Control between Continuous Regular Insulin Infusion and Single-dose Subcutaneous Insulin Glargine Injection in Medical Critically Ill Patients.

Background and Aims:This study aimed to compare glycemic control between continuous intravenous regular insulin infusion and single-dose subcutaneous insulin glargine injection in medical critically ill patients.Subjects and Methods:A prospective noninferiority study was conducted in medical critically ill patients who developed hyperglycemia and required regular insulin infusion by the Intensive Care Unit glycemic control protocol. The eligible patients were switched from the daily regular insulin requirement to single-dose subcutaneous insulin glargine injection by a 100% conversion dose. Arterial blood glucose was checked every 2 h for 24 h. Success cases were blood glucose levels of 80–200 mg/dL during the study period. The mean time-averaged area under the curves (AUCs) of blood glucose levels between the two types of insulin were compared by t-test.Results:Of 20 cases, 14 cases (70%) were successful. The mean time-averaged AUCs of blood glucose levels between the two types of insulin were not significantly different (155.91 ± 27.54 mg/dL vs. 151.70 ± 17.07 mg/dL, P = 0.56) and less than the predefined noninferior margin. No severe hypoglycemic cases were detected during the study period.Conclusions:Single-dose subcutaneous insulin glargine injection was feasibly applied for glycemic control in medical critically ill patients. The glycemic control in the critically ill patients by a single dose of subcutaneous insulin glargine was comparable to standard intravenous regular insulin infusion. A conversion dose of 100% of the daily requirement of regular insulin is suggested.

Results of interim analysis of the multicenter randomized phase III SENORITA trial of laparoscopic sentinel node oriented, stomach-preserving surgery versus laparoscopic standard gastrectomy with lymph node dissection in early gastric cancer.

4028 Background: The benefits and hazards of laparoscopic sentinel node oriented stomach-preserving surgery, compared to those of laparoscopic standard gastrectomy with lymph node dissection in early gastric cancer (EGC), are unknown. The SENORITA trial investigated the clinical impact of laparoscopic sentinel node oriented stomach-preserving surgery in EGC. Methods: Other than those with absolute indication for endoscopic resection, eligible patients had EGC confined to the mucosa and submucosa, with diameter ≤ 3cm, regardless of histology on preoperative evaluation. Patients were randomized for laparoscopic standard gastrectomy or laparoscopic stomach-preserving surgery. Patients were stratified based on depth (mucosa vs. submucosa) and size (≤ 2cm vs. 2 &lt; ≤ 3cm) of the EGC and by participating institution. The primary endpoint was 3-year disease-free survival (3yDFS). The expected 3yDFS was 97% and non-inferior margin was 5%. 580 patients and 24 events were needed to show non-inferiority with 80% power. One interim analysis was planned after 12 events (50%) occurred. Using the O’Brien-Fleming error spending function, the two-sided nominal significance level for the interim analysis would be 0.0054. Results: From March 2013 to May 2016 462 patients were randomized; analysis was performed in 421 after a dropout of 41 patients. Laparoscopic stomach-preserving surgery was possible in 75.6% by study protocol. Interim analysis was conducted based on 12 events (median follow-up: 15.89 months). The 3yDFS in the laparoscopic standard gastrectomy arm was 96%; the 3yDFS in the laparoscopic stomach-preserving surgery arm was 93%, (99.46% CI: -3.18%, 9.18%). The postoperative complication rates were 15.0% and 12.9%, respectively (p = 0.542). Conclusions: In this interim analysis, laparoscopic sentinel node oriented stomach-preserving surgery did not show non-inferiority for 3yDFS. The follow-up time was not mature enough to evaluate non-inferiority. Further follow-up will elucidate the role of laparoscopic sentinel node oriented stomach-preserving surgery. Clinical trial information: NCT01804998.

1093P - Switch maintenance therapy with racotumomab or nimotuzumab vs docetaxel for NSCLC patients

Maintenance therapy is a common strategy in NSCLC treatment that improves PFS and OS. Racotumomab-alum is an anti-idiotypic vaccine that induces immunological response against N-glycolilated gangliosides in NSCLC patients. Nimotuzumab is a humanized anti-EGFR monoclonal antibody that has shown activity in NSCLC patients. The aim of this study is to evaluate safety and efficacy of racotumomab-alum or nimotuzumab versus docetaxel as second line or switch maintenance therapy for advanced NSCLC. This phase III, multicenter, open label, randomized trial is designed to enroll 743 stage IIIB-IV NSCLC patients, after first line therapy, with PS 0-2, with written informed consent. The primary endpoint is OS. Patients are been randomized (2:2:1) to 3 arms: racotumomab-alum, nimotuzumab or docetaxel, and stratified according to response to first line. Racotumomab-alum treatment consists in 5 bi-weekly intradermal doses and re-immunizations every 4 weeks. Nimotuzumab arm receives 6 weekly infusions followed by bi-weekly doses. Docetaxel is used at 75 mg/m2 for 6 cycles, if there are no evidences of progressive disease after 3 cycles. As switch maintenance therapy, both experimental drugs will be classified as non-inferior (NI) to docetaxel, if 1- year OS rate is 36% (HRC/T = 0.66) [ d0 (0,41), d0= - ln HR(C/T)] using a 15% NI margin. Here we report the final analysis in non-progressor patients (n = 237). 93 patients in each experimental arm and 51 in docetaxel arm with at least 1 year follow up were analyzed (ITT). The median OS and 1-year survival rate were 11.4 months (CI: 7.07-12.46) and 48.3 % with nimotuzumab, 9.67 months (CI: 6.52-12.82) and 45.5 % with racotumomab-alum and 9.76 months (CI: 7.07-12.46) and 33.5 % with docetaxel, respectively. Most frequent treatment-related adverse events were induration, local erythema and pain in injection site with racotumomab-alum; myalgia, nausea and fever with Nimotuzumab, and anemia, nausea and malaise after docetaxel. Racotumomab-alum [CI 90% NI (-∞;0.14)] and Nimotuzumab [CI 90% NI (- ∞; -0.002) are non-inferior to docetaxel as switch maintenance therapy. Both experimental treatments were safely administered at primary level of health assistance.

A randomised, open-label study of umeclidinium versus glycopyrronium in patients with COPD.

This study compared the efficacy and safety of once-daily umeclidinium 62.5 µg with once-daily glycopyrronium 50 µg in patients with moderate-to-severe chronic obstructive pulmonary disease.This was a 12-week, multicentre, randomised, open-label, parallel-group study (Clinicaltrials.gov: NCT02236611). Patients were randomised 1:1 to umeclidinium 62.5 µg or glycopyrronium 50 µg administered via Ellipta or Breezhaler dry powder inhaler, respectively. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at day 85 in the per-protocol population. Other endpoints included: weighted mean FEV1 over 0–24 h and patient-reported outcomes (transition dyspnoea index score and St George's Respiratory Questionnaire total score). Adverse events were also assessed.A total of 1037 patients were randomised to treatment. Umeclidinium was non-inferior (margin: −50 mL) to glycopyrronium (trough FEV1 at day 85 treatment difference: 24 mL, 95% confidence intervals: −5–54). Improvements in other endpoints were similar between treatments. Adverse event incidences were similar for umeclidinium (37%) and glycopyrronium (36%).Once-daily umeclidinium was non-inferior to once-daily glycopyrronium in patients with chronic obstructive pulmonary disease in trough FEV1 at day 85. Patient-reported outcomes and safety profiles were similar for both treatments.

Comparative study of the efficacy of limaprost and pregabalin as single agents and in combination for the treatment of lumbar spinal stenosis: a prospective, double-blind, randomized controlled non-inferiority trial

Background ContextAlthough the simultaneous management of neuronal ischemia-related pain and compression-demyelination–related neuropathic pain is considered optimal in treating lumbar spinal stenosis (LSS), the effect of combination therapy with pregabalin and limaprost has not been elucidated. PurposeThis study aimed to compare the effects of limaprost and pregabalin individually and in combination for the treatment of LSS. Study DesignThis is a prospective, double-blind, double-dummy, randomized controlled trial. Patient SampleThe sample consists of patients with LSS. Outcome MeasuresThe baseline-adjusted Oswestry Disability Index (ODI) score, visual analog scale (VAS) scores for leg pain, the European Quality of Life-5 dimensions (EQ-5D), and initial claudication distance (ICD). MethodsThe present study (ClinicalTrials.gov, number NCT01888536) was a prospective, double-blind, double-dummy, randomized controlled trial designed to determine the efficacy of limaprost in alleviating leg pain, improving disability, and increasing walking distance in persons with degenerative LSS in three different treatment groups: limaprost alone, pregabalin alone, and combined limaprost and pregabalin through 1:1:1 allocation. The primary outcome was the baseline-adjusted ODI score at 8 weeks after treatment. The non-inferior margin of the ODI was set at δ=10 points. ResultsThe baseline-adjusted ODI score (primary outcome) at 8 weeks after treatment in the limaprost group was not inferior to those in the pregabalin and limaprost+pregabalin groups. The overall changes of the baseline-adjusted ODI scores, VAS scores for leg pain, the EQ-5D, and ICD during the follow-up assessments over an 8-week period (secondary end point) were not different among the three groups. The baseline-adjusted ODI scores and VAS scores for leg pain decreasedsignificantly over time after treatment in all three groups. The baseline-adjusted EQ-5D score and ICD also increased significantly over time after treatment in all three groups. ConclusionsThe efficacy of limaprost for lumbar spinal stenosis was not inferior compared with that of pregabalin or the combination of limaprost and pregabalin in terms of disability. Therefore, combined treatment with limaprost and pregabalin does not provide additional relief in symptoms in patients with LSS compared with monotherapy with limaprost or pregabalin.