Good Clinical Practice Guidelines Research Articles

Immunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial

SummaryBackgroundFew data are available to support the choice between the two currently available pneumococcal conjugate vaccines (PCVs), ten-valent PCV (PCV10) and 13-valent PCV (PCV13). Here we report a head-to-head comparison of the immunogenicity and reactogenicity of PCV10 and PCV13.MethodsIn this parallel, open-label, randomised controlled trial, healthy infants from two districts in Ho Chi Minh City, Vietnam, were randomly allocated (in a 3:3:5:4:5:4 ratio), with use of a computer-generated list, to one of six infant PCV schedules: PCV10 in a 3 + 1 (group A), 3 + 0 (group B), 2 + 1 (group C), or two-dose schedule (group D); PCV13 in a 2 + 1 schedule (group E); or no infant PCV (control; group F). Blood samples were collected from infants between 2 months and 18 months of age at various timepoints before and after PCV doses and analysed (in a blinded manner) by ELISA and opsonophagocytic assay. The trial had two independent aims: to compare vaccination responses between PCV10 and PCV13, and to evaluate different schedules of PCV10. In this Article, we present results pertaining to the first aim. The primary outcome was the proportion of infants with an IgG concentration of at least 0·35 μg/mL for the ten serotypes common to the two vaccines at age 5 months, 4 weeks after the two-dose primary vaccination series (group C vs group E, per protocol population). An overall difference among the schedules was defined as at least seven of ten serotypes differing in the same direction at the 10% level. We also assessed whether the two-dose primary series of PCV13 (group E) was non-inferior at the 10% level to a three-dose primary series of PCV10 (groups A and B). This trial is registered with ClinicalTrials.gov, number NCT01953510.FindingsOf 1424 infants screened between Sept 30, 2013, and Jan 9, 2015, 1201 were allocated to the six groups: 152 (13%) to group A, 149 (12%) to group B, 250 (21%) to group C, 202 (17%) to group D, 251 (21%) to group E, and 197 (16%) to group F. 237 (95%) participants in group C (PCV10) and 232 (92%) in group E (PCV13) completed the primary vaccination series and had blood draws within the specified window at age 5 months, at which time the proportion of infants with IgG concentrations of at least 0·35 μg/mL did not differ between groups at the 10% level for any serotype (PCV10–PCV13 risk difference −2·1% [95% CI −4·8 to −0·1] for serotype 1; −1·3% [–3·7 to 0·6] for serotype 4; −3·4% [–6·8 to −0·4] for serotype 5; 15·6 [7·2 to 23·7] for serotype 6B; −1·3% [–3·7 to 0·6] for serotype 7F; −1·6% [–5·1 to 1·7] for serotype 9V; 0·0% [–2·7 to 2·9] for serotype 14; −2·1% [–5·3 to 0·9] for serotype 18C; 0·0% [–2·2 to 2·3] for serotype 19F; and −11·6% [–18·2 to −4·9] for serotype 23F). At the same timepoint, two doses of PCV13 were non-inferior to three doses of PCV10 for nine of the ten shared serotypes (excluding 6B). Reactogenicity and serious adverse events were monitored according to good clinical practice guidelines, and the profiles were similar in the two groups.InterpretationPCV10 and PCV13 are similarly highly immunogenic when used in 2 + 1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings.FundingNational Health and Medical Research Council of Australia, and Bill & Melinda Gates Foundation.

Skin antisepsis with chlorhexidine–alcohol versus povidone iodine–alcohol, combined or not with use of a bundle of new devices, for prevention of short-term peripheral venous catheter-related infectious complications and catheter failure: an open-label, single-centre, randomised, four-parallel group, two-by-two factorial trial: CLEAN 3 protocol study

IntroductionShort peripheral intravenous catheters (PVCs) are the most frequently used invasive medical devices in hospitals. Unfortunately, PVCs often fail before the end of treatment due to the occurrence of mechanical,...

Allogeneic Transplantation in Multiple Myeloma: Long-Term Follow-Up and Cytogenetic Subgroup Analysis

Background: Allogeneic (allo) following autologous (auto) stem-cell transplantation (SCT) has yielded conflicting results in newly diagnosed multiple myeloma (MM). In alloSCT, information is lacking regarding the impact of cytogenetic features except chromosome 13q deletion (del13q). Methods: This phase 3 trial compared tandem autoSCT versus autoSCT followed by reduced-intensity conditioning alloSCT (auto/alloSCT) in del13q MM. The availability/absence of a human leukocyte antigen-matched related or matched unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intent-to-treat population (n=199). Findings: Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months' median follow-up (range 2-143 months), median PFS with auto/allo versus tandem autoSCT was 34·5 versus 21.8 months (p=0·003; adjusted hazard ratio 0·55, 95% confidence interval [CI] 0·36-0·84). Median overall survival (OS) was 70.2 versus 71.8 months (p=0.856). Two-year non-relapse mortality (NRM) with auto/allo versus tandem autoSCT was 14·3% versus 4·1% (p=0·008). In patients harbouring both del13q and deletion of chromosome 17p, median PFS and OS were 37·5 and 61·5 months with auto/allo (n=19) versus 6·1 and 23·4 months with tandem autoSCT (n=6) (p=0·0002 and 0·032). Interpretation: Auto/alloSCT significantly extends PFS versus tandem autoSCT in patients with del13q MM. We believe this to be the first MM study demonstrating that MUD alloSCT can be performed with reasonable NRM. Furthermore, our data suggest some survival benefit for first-line alloSCT in high-risk MM. Funding: The trial was sponsored by Wurzburg University, Wurzburg, Germany. Declaration of Interest: MH reports personal fees from Amgen, Celgene, Janssen, Bristol-Myers Squibb, and Takeda. GH reports personal fees from Janssen, Roche, AbbVie, Gilead, Novartis, MorphoSys, and Celgene; and grants from Roche, Pfizer, and Celgene. SM reports non-financial support from EBMT/EHA, IACH, Celgene, Miltenyi, KIADIS, Bellicum, DGHO, Jazz Pharma, and ISCT; and personal fees from Celgene, Miltenyi, KIADIS, Bellicum, and Jazz Pharma. GM reports personal fees from Gilead, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck-Serono; and non-financial support from Janssen-Cilag. LK reports honoraria for presentation at “MedIpdate” (OnkoUpdate, IntemistenUpdate, PraxisUpdate) and at “Medizin Aktuell”. Amgen and Celgene are sponsors of the “Biannual International Stem Cell Conference, Tubingen, Germany): Scientific chairman: LK. HE reports grants, personal fees, and other (advisory board) from Janssen, Celgene, Amgen, BristolMyers Squibb, Novartis, and Takeda. All other authors declare no competing interests. Ethical Approval: The trial protocol was approved by the Wurzburg University ethics committee. All patients provided written informed consent prior to trial entry, and all procedures were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice.

Where there is no evidence: implementing family interventions from recommendations in the NICE guideline 11 on challenging behaviour in a South African health service for adults with intellectual disability

BackgroundLow- and middle-income countries often lack the fiscal, infrastructural and human resources to conduct evidence-based research; similar constraints may also hinder the application of good clinical practice guidelines based on research findings from high-income countries. While the context of health organizations is increasingly recognized as an important consideration when such guidelines are implemented, there is a paucity of studies that have considered local contexts of resource-scarcity against recommended clinical guidelines.MethodsThis paper sets out to explore the implementation of the NICE Guideline 11 on family interventions when working with persons with intellectual disability and challenging behavior by a group of psychologists employed in a government health facility in Cape Town, South Africa.ResultsIn the absence of evidence-based South African research, we argue that aspects of the guidelines, in particular those that informed our ethos and conceptual thinking, could be applied by clinical psychologists in a meaningful manner notwithstanding the relative scarcity of resources.ConclusionWe have argued that where guidelines such as the NICE Guidelines do not apply contextually throughout, it remains important to retain the principles behind these guidelines in local contexts. Limitations of this study exist in that the data were drawn only from the clinical experience of authors. Some of the implications for future research in resource-constrained contexts such as ours are discussed. Smaller descriptive, qualitative studies are necessary to explore the contextual limitations and resource strengths that exist in low- and middle-income settings, and these studies should be more systematic than drawing only on the clinical experience of authors, as has been done in this study.

Effect of imipramine on urethral opening pressure: A randomized, double-blind, placebo-controlled crossover study in healthy women.

In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry. A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department. There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06. In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.

PACMAN trial protocol, Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac major surgery: a randomised, multicentre, double-blind, superiority study

IntroductionPostoperative complications are major healthcare problems and are associated with a reduced short-term and long-term survival after surgery. An excessive postoperative inflammatory response participates to the development of postoperative infection...

Health-Related Quality of Life in Transplant Ineligible Newly Diagnosed Multiple Myeloma Patients Treated with Either Thalidomide or Lenalidomide-Based Regimen Until Progression (HOVON-87/NMSG18 Study): A Prospective, Open-Label, Multicenter, Randomized, Phase 3 Study

Background: The overall survival of patients with Multiple Myeloma has improved due to effective, often continuous, therapy. However, knowledge on the impact of long term treatment on health-related quality of life (HRQoL) is limited. Methods: The HOVON87/NMSG18 study was a prospective, randomized, phase 3 study of newly diagnosed transplant ineligible multiple myeloma patients, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by thalidomide or lenalidomide maintenance therapy (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed by patients at baseline, after 3 and 9 induction cycles and after 6 and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for between and within treatment arm HRQoL evaluation. Findings: 596 of 637 eligible patients participated in HRQoL reporting. Patients in both arms reported clinical relevant improvement in global QoL, future perspective, role and emotional functioning and the summary score, and less fatigue and pain, in general occurring after 6 to 12 months of maintenance only and independent of WHO performance at baseline. MPR-R treated patients reported clinically relevant worsening of diarrhoea and MPT-T treated patients reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least 3 months reported clinically meaningful improvement in global QoL, role functioning and the summary score over time, without any clinical meaningful deteriorations. In contrast, patients on thalidomide reported clinically relevant worsening of peripheral neuropathy. Interpretation: Treatment with both thalidomide- and lenalidomide-based regimens improved HRQoL, in general reaching clinical relevance during maintenance therapy only. Clinical relevant diarrhea was reported by lenaldiomide-treated and clinical relevant PNP by thalidomide-treated patients. Trial Registration Number: The study was registered at www.trialregister.nl NTR1630. Funding Statement: Dutch Cancer Society KWF VU-2008 4246, Celgene Declaration of Interests: AW reports that the study was supported by Celgene and receives honoraria Takeda and grant from Amgen. MH reports compensation for work related to the study from NTNU Department of Cancer Research and Molecular Medicine and receives grant from Celgene Aps. MS receives personal fees from Celgene, Amgen, Janssen and Takeda. SZ receives research funding from Celgene, Janssen, Takeda and Amgen and serves on advisory board for Celgene, Janssen, Takeda and Amgen. LKN has received grants from Celgene, Janssen, Amgen and Takeda, during the conduct of the study. NA receives research funding from Celgene, Janssen, Takeda and Amgen. PS receives grants from Takeda, Karyopharma, and grants and personal fees from Celgene, Janssen-Cilag. M-DL has received personal fees from Celgene. U-HM has received lecture honoraria from Amgen, Takeda, Janssen, Mundipharma, Oncopeptides and serves on advisory board for Amgen. NvdD receives grants from Celgene, Janssen pharmaceuticals, Novatis, Amgen and BMS and serves at the advisory board for Celgene, Janssen pharmaceuticals, Novartis, Amgen, Takeda, BMS, Bayer, Servier. All other authors declare no conflicting interest. Ethics Approval Statement: The study protocol was approved by the Ethics Committee and conducted in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines. The authors obtained written informed consent from all participants.

A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2)

IntroductionSepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist....

Evaluating Optical Coherence Tomography (OCT) Findings as Potential Biomarkers in Central Nervous System (CNS) Lymphoma with or Without Ocular Involvement

Purpose: To evaluate spectral domain optical coherence tomography (SD-OCT) findings as potential biomarkers in primary central nervous system lymphoma (PCNSL) with or without ocular involvement. Methods: The patient cohort finder tool at Stanford University Hospital was used to identify patients with any type of lymphoma using the ICD-10 codes (C82-C88), from January 2004 to October 2017. A total of 14,820 patients were identified. Procedure code (92134) for optical coherence tomography (OCT) was then applied to identify patients who underwent OCT at the ophthalmology clinic/Byers Eye Institute. Clinic charts of 460 patients with lymphoma who had undergone OCT were reviewed to identify patients with confirmed diagnosis of PCNSL and divided into two groups (Group 1: with and Group 2: without ocular involvement). Their SD-OCTs from within 1 month of the diagnosis were analyzed for the presence of 1) Hyperreflective deposits in choroid, retinal pigment epithelium (RPE), outer retina and inner retina; 2) RPE thickening; 3) Vitreous debris; 4) Intraretinal fluid; 5) Ellipsoid zone disruption by masked graders. Chi-square was used to analyze the difference in characteristics between the groups. Results: Twenty-two eyes of 11 patients with PCNSL were included this study (6 eyes in group 1 and 16 eyes in group 2). Mean age of subjects was 65 years (Group1: 60 years and Group 2: 67 years). Five patients (45.45%) were female (Group1: 3 and Group2: 7). There was no statistically significant difference between the groups for the presence of hyperreflective deposits in choroid, RPE, outer and inner retina, and the presence of RPE thickening, intraretinal fluid and ellipsoid zone disruption. Vitreous debris was found more commonly in group 1 subjects (83%) than group 2 (31.25%) (p=0.029). All subjects in both groups showed hyperreflective deposits in the RPE demonstrating RPE infiltration. However, RPE thickening was noted only in 3 patients (Group1: 1 and Group2: 2). Conclusions: Our study has demonstrated that the OCT findings of hyperreflective deposits present in eye with IOL secondary to PCNSL are also observed in eyes with PCNSL without ocular disease. These hyperreflective deposits can serve as biomarkers and aid in the early detection of ocular involvement by PCNSL. Funding Statement: funding was received for this project Declaration of Interests: QDN is a recipient of a Physician Scientist Award from Research to Prevent Blindness, New York, NY, and serves on the Scientific Advisory Board for AbbVie, Bayer, Genentech, Regeneron, and Santen, among others. No other authors have received any financial funding or support. The Byers Eye Institute has received research funding support from Research Prevent Blindness, Inc. Ethics Approval Statement: It was conducted in compliance with the Declaration of Helsinki, the United States Code of Federal Regulations Title 21, and the Harmonized Tripartite Guidelines for Good Clinical Practice (1996). The study was approved by local institutional review board. An informed consent waiver was obtained as charts of the selected patients were reviewed retrospectively.

Multicentre randomised controlled trial to investigate usefulness of the rapid diagnostic βLACTA test performed directly on bacterial cell pellets from respiratory, urinary or blood samples for the early de-escalation of carbapenems in septic intensive care unit patients: the BLUE-CarbA protocol

IntroductionThe dramatic increase of the incidence of infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has led to an increase of 50% of carbapenem consumption all around Europe in only 5...

The Resistance Landscape of Abivertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, and Clinical Strategy to Overcome Resistance in EGFR T790M-Positive Non-Small Cell Lung Cancer

Background: Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC). Here, we report resistance mechanisms to abivertinib, a novel third-generation EGFR TKI, from a phase I dose-escalation/expansion study (NCT02330367), and describe clinical strategies to overcome EGFR amplification-mediated resistance. Methods: Patients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR TKIs received abivertinib in dose escalation (50-350 mg twice daily [BID]) or expansion (300 mg BID) cohorts. Patients enrolled at Guangdong Lung Cancer Institute who underwent next-generation sequencing-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis. Findings: Thirty-two of 73 patients enrolled were eligible for resistance analysis. A heterogeneous landscape of resistance mechanisms to abivertinib was observed with 14% (4/28) experiencing EGFR T790M loss and 13% (4/32) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (34%), and considered a putative resistance mechanism in seven (22%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation. We demonstrated that abivertinib plus nimotuzumab or afatinib is effective and tolerable in overcoming EGFR amplification-mediated resistance to abivertinib. Interpretation: Our findings reveal a heterogenous pattern of resistance mechanisms to abivertinib which is distinct from that previously reported with osimertinib. EGFR amplification was the most common resistance mechanism in this cohort and may be overcome by combining abivertinib with an EGFR monoclonal antibody or afatinib. Funding: This work was supported by The National Key R&D Program of China (Grant No. 2016YFC1303800, to Q Zhou), Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational 447 Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120, to YL WU). Medical writing support was provided by Siân Marshall PhD, SIANTIFIX Inc., Cambridge, UK, funded by ACEA Therapeutics Inc. Declaration of Interest: QZ declares grants from National Key R&D Program of China, speaker fees from AstraZeneca and Roche. Y-LW declares grants from Key Lab System Project of Guangdong Science and Technology Department, speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. XX is the CEO and stock owner of ACEA Therapeutics Inc. WT, FRL are employees of ACEA Therapeutics Inc. S-KC, J-YY, H-ZH, ZZ are employees of Burning Rock Biotech. Other authors declare no competing interests. Ethical Approval: This study was approved by the ethics committee at Guangdong General Hospital, and all patients provided written, informed consent. The study adhered to the principles of Declaration of Helsinki and the Good Clinical Practice guidelines.

Factors associated with adherence to guidelines of good clinical practice during hospital treatment of patients with the first episode of schizophrenia spectrum disorders

Background/Aim. Adherence to the guidelines of Good Clinical Practice (GCP) during the treatment of specific disorders is considered a guarantee of the implementation of a uniform, evidence-based clinical practice in psychiatry. The aim of this study was to analyze the concordance of prescribing patterns of antipsychotic drugs with the recommendations of good clinical practice in Serbia and an insight into the effects that introduction of the National Guideline for the Diagnosis and Treatment of Schizophrenia had on the prescribing practice in this area. Methods. Noninterventional, observational study was conducted at the Clinic for Mental Disorders ?Dr Laza Lazarevic? in Belgrade. It included a consecutive sample of 675 previously untreated patients, hospitalized from January 1st, 2012 to December 31st, 2015, dismissed with a discharge diagnosis of any of schizophrenia spectrum disorders. The data about demographic and clinical characteristics of patients, characteristics of prescribers and prescribed antipsychotics were obtained retrospectively, from the patients? medical records. For the analysis of primary data, the descriptive statistical methods and methods for testing statistical hypotheses were used. A method of logistic regression was used to identify the factors associated with adherence to the GCP recommendations. Results. Totaly, 446 (66.1%) of subjects were treated with antipsychotic monotherapy. After the introduction of National Guideline for the Diagnosis and Treatment of Schizophrenia prescribing of second generation antipsychotic monotherapy (78.41% vs. 63.5%, respectively; p < 0.001) increased significantly compared to the previous period. The factors independently associated with adherence to the recommendations of the GCP were the year of hospitalization, the age of the prescriber, and the age and education of the patient. Conclusion. After the introduction of the National Guide to Good Clinical Practice for the Diagnosis and Treatment of Schizophrenia there have been significant, but insufficient changes in the prescribing patterns of antipsychotics during the treatment of the first psychotic episode in Serbia.

Dijagnostičke greške u porodičnoj medicini

Introduction: The diagnosis of disease is an important and often complex process. In the diagnostic process the doctor is obliged to abide by the rules of the medical methodology, that is, to follow the algorithm that prescribes the guidelines of good clinical practice. Diagnostic errors include missed, delayed or incorrect diagnoses. They arise as a result of failure to comply with a diagnostic protocol or an inadequate interpretation of the findings obtained during the same. Case Report: A patient born in 1953 who is not registered with the Health Center Krupa na Uni comes from the ambulance family medicine. He brought with him a stone that erupted two days ago. Problems with stones in the barrel have been back for six years. Annually there is one episode of the kidney colic, which in the course of therapy is prescribed drugs from the group Fluoroquinolone and analgesics, he erodes the stone and it is good. He states that he has done six blood and urine tests, two ultrasound examinations of the abdomen and one consultation with a urologist. He is worried that his sedimentation has been constantly increased and the fact that at the last ultrasound examination he was told that one kidney was only doing 20%. Ultrasound examination at the Health Center Krupa na Uni reveals a large tumour lesion of 8 cm diameter in the area of the sigmoid colon that bends to the bladder and metastatic changes to the II, V, VI and VII liver segments. The pathohistological finding was described by adenocarcinoma invasivum interstini crassi gradus II pT4N1cM1a. After the XELOX protocol (eight therapeutic regimens) was performed, chemotherapy resulted in withdrawal of metastatic changes. Conclusion: Respecting good clinical practice guidelines, careful medical documentation, continuous medical education and quality communication with the patient make it possible to carry out the medical profession safely with minimum risk for the diagnosis of the diagnosis.

Efficacy and Safety of CT-P13 in Inflammatory Bowel Disease after Switching from Originator Infliximab: Exploratory Analyses from the NOR-SWITCH Main and Extension Trials

Background: TNF-alpha inhibitors have improved treatment of chronic immune-mediated inflammatory disorders. The NOR-SWITCH main and extension trial addressed switching from infliximab originator (IFX) to CT-P13 across six diseases. Here we present the exploratory post-hoc analyses in Crohn's disease (CD) and ulcerative colitis (UC). Methods: The 52-week, randomized, non-inferiority, double blind, multicenter, phase 4 NOR-SWITCH study was followed by a 26-week open extension trial where all patients received treatment with CT-P13. Treatment efficacy, safety and immunogenicity were assessed throughout the 78-week study period. The primary endpoint was disease worsening. Findings: The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. The baseline characteristics were comparable between treatment arms in both diseases. Disease worsening in the main trial occurred in 14 (21%) of CD patients in the IFX group and 23 (37%) in the CT-P13 group (risk difference -14⋅3%, CI -29⋅3 to 0⋅7). In the extension study, disease worsening occurred in 13 (21%) patients in the CT-P13 maintenance group and 8 (13%) in the IFX/CT-P13 switch group (risk difference 7⋅9%, CI -5⋅2 to 21). The corresponding results in UC were 3 (9%) and 5 (12%) patients (risk difference -2⋅6%, CI -15⋅2 to 10⋅0) in the main trial, and 6 (15%) and 1 (3%) patients (risk difference 12⋅4%, CI -0⋅1 to 25⋅0) in the extension trial. In both diseases, the treatment groups were similar across disease activity measures, drug levels and immunogenicity. Interpretation: The subgroup analyses of IBD in the NOR-SWITCH main and extension trials support switching from originator infliximab to CT-P13 for non-medical reasons. Trial Registration: ClinicalTrials.gov NCT-02148640, EudraCT Number: 2014-002056-40. Funding Statement: This work was supported by the Norwegian Ministry of Health and Care Services. Declaration of Interests: KKJ reports personal fees from Intercept, Norgine and Celltrion. GLG reports personal fees from AbbVie, Biogen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Orion Pharma, Celltrion and Boehringer Ingelheim. NB reports personal fees received from Orion Pharma, Roche, Napp Pharmaceuticals, Pfizer, and Takeda. ICO reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study, and personal fees from Pfizer. EAH reports grants from AbbVie, Pfizer, UCB, Roche, and MSD. IPB reports personal fees from AbbVie, MSD, Takeda, Hospira, and Ferring. KEAL reports grants from MSD, personal fees from Takeda, Orion, Abbvie, Pfizer, and MSD. JJ reports personal fees from MSD, AbbVie, Celltrion, Orion Pharma, Takeda, Napp Pharm, AstroPharma, Hikma and Pfizer. TKK reports reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study and personal fees from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, and UCB Pharma. SOF reports personal fees from Takeda, Pharmacosmos, Tillotts, Janssen, Intercept and Pfizer. Ethics Approval Statement: The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study protocol and consent documents were approved by an independent ethics committee (Regional Committees for Medical and Health Research Ethics South East; reference number 2014/848), by appropriate institutional review boards and by the Norwegian Medicines Agency (reference number 14/07192-11).

Treatment of Primary Aldosteronism with mTORC1 Inhibitors

Primary aldosteronism is the most frequent cause of endocrine hypertension. It is characterized by inappropriately high and relatively autonomous aldosterone production by the adrenal cortex Treatment of primary aldosteronism by unilateral adrenalectomy or mineralocorticoid receptor antagonists is not always well tolerated, and targeted pharmacological aldosterone-lowering therapies are still lacking. The adrenal cortex of patients with primary aldosteronism commonly shows increased mTORC1 activity, and mTORC1 inhibition decreases aldosterone production in adrenocortical cells. Here, we show that treatment of mice with rapamycin decreases plasma aldosterone levels, without affecting other steroid hormones. Furthermore, treatment of patients affected by primary aldosteronism with everolimus significantly decreased blood pressure and increased renin levels along with a reduction in aldosterone levels in a subset of patients. These findings suggest a role of mTORC1 in primary aldosteronism and that a subset of patients with this condition may benefit from drugs targeting the mTORC1 pathway. Clinical Trial Number: The trial was registered at Clinicaltrials.gov (NCT03174171) Funding Statement: M.N.H. and M.M.S. received funding from Novartis Foundation for Medical Biological Research, M.M.S. received funding from Novartis/University of Basel Excellence Scholarship for Life Sciences. A.O. received funding from the Swiss National Science Foundation (31003A179400). FB and MR have been supported by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease“ and by the Else Kroner-Fresenius Stiftung (2013_A182 and 2015_A171 to MR). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was approved by the regional ethical committee (EKNZ 2015-400) and Swissmedic (2017DR2062), and was conducted in accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. All animal experiments were approved by the Kantonales Veterinaramt of Kanton Basel-Stadt (Basel, Switzerland).

Epacadostat Plus Pembrolizumab versus Placebo Plus Pembrolizumab in Patients with Unresectable or Metastatic Melanoma: Results of the Phase 3, Randomised, Double-Blind Echo-301/Keynote-252 Study

Epacadostat Plus Pembrolizumab versus Placebo Plus Pembrolizumab in Patients with Unresectable or Metastatic Melanoma: Results of the Phase 3, Randomised, Double-Blind Echo-301/Keynote-252 Study

Pembrolizumab Plus Chemotherapy as Neoadjuvant Treatment for Locally Advanced Triple-Negative Breast Cancer: Results from the Phase 1b Open-Label, Multicohort KEYNOTE-173 Study

Background: The phase 1b KEYNOTE-173 study assessed the safety and preliminary antitumour activity of neoadjuvant chemotherapy plus pembrolizumab in locally advanced non-metastatic triple-negative breast cancer (TNBC). Methods: Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), followed by 8 cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks and then doxorubicin and cyclophosphamide for additional 12 weeks before surgery. Primary endpoints were safety and recommended phase 2 dose (RP2D); secondary endpoints were pathological complete response (pCR) rate, objective response rate (ORR), event-free and overall survival. Exploratory endpoints included the relationship between outcome and potential biomarkers, such as tumour programmed death ligand 1 (PD-L1) expression (combined positive score [CPS]) and stromal tumour-infiltrating lymphocyte levels (sTILs). Study is registered with ClinicalTrials.gov, NCT02622074. Findings: Sixty patients were enrolled between February 18, 2016 and February 28, 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n=9 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold, whereas 2 cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%), which were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range, 30%–80%). 12-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 CPS, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively). Interpretation: The combination of neoadjuvant chemotherapy with pembrolizumab for locally advanced TNBC showed manageable toxicity and promising antitumour activity. In an exploratory analysis, pCR rate showed positive correlation with tumour PD-L1 expression and sTIL levels. Funding: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Declaration of Interest: PS has received grants from AstraZeneca, Roche, Genentech, Oncogenex, Novartis, Astellas and consulting fees from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, and Puma Biotechnology. His spouse has received consulting fees from Genentech and Roche. RS received research support for the scoring of sTILs presented in this manuscript. YHP has received grants, personal fees and non-financial support from Pfizer, Eisai, and Roche, personal fees and nonfinancial support from Merck, grants and personal fees from Novartis, personal fees from Celgene, and non-financial support from Hanmi. SBK has received grants from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc, and DongKook Pharm Co and has received consulting fees from Novartis, AstraZeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, and Daiichi-Sankyo. JS has received grants from Merck, Roche, Novartis, AstraZeneca, Lilly, Pfizer, Bayer, GlaxoSmithKline, CONTESSA, and Daiichi Sankyo. TF has received grants and consulting fees (as institutional payments) from Pfizer, grants from Roche, and royalties for authorship from Wolters Kluwer Health (UpToDate). SK has received personal fees from Roche, Genomic Health, Lilly, Novartis, Amgen, Celgene, Daiichi Sankyo, AstraZeneca, Somatex, Merck, Pfizer, Puma Biotechnology, and PFM Medical and non-financial support from Roche and Daiichi Sankyo. RD has received personal fees from AstraZeneca, Eisai, Lilly, Merck, Novartis, Pfizer, Roche, and Seattle Genetics. JC has received grants (as institutional payments) from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck, Pfizer, Piqur Therapeutics, Puma Biotechnology, Queen Mary University of London, and Seagen, consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck, GlaxoSmithKline, and Leuko, and honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck, and Daiichi Sankyo. SL has received grants (as institutional payments) from Novartis, Bristol-Myers Squibb, Merck, Roche-Genentech, Puma Biotechnologyand Eli Lilly, has acted as a consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech and has received consulting fees (to institution) from Aduro Biotech. EMC has nothing to disclose. LY, AW, KT, and VK are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Ethical Approval: The study protocol was approved by the appropriate institutional review board or independent ethics committee at each participating institution. The study was conducted in accordance with the protocol, good clinical practice guidelines, provisions of the Declaration of Helsinki and all local regulations. All patients provided written informed consent to participate.

Long-Term Outcomes in Patients with PET-Predicted Poor-Responsive HER2-Positive Breast Cancer Treated with Neoadjuvant Bevacizumab Added to Trastuzumab and Docetaxel: 5-Year Follow-Up of the Randomised AVATAXHER Study

Background: The open-label, randomised Phase 2 AVATAXHER study demonstrated that early PET assessment identified patients with HER-2 positive breast cancer who responded poorly to standard neoadjuvant therapy (docetaxel plus trastuzumab). Adding bevacizumab to neoadjuvant therapy in PET-predicted poor-responders improved pathological complete response (pCR) rates (from 24·0% to 43·8%). We investigated whether the improved pCR rate translated into improved long-term outcomes. Methods: Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹⁸F]-FDG PET conducted before each cycle. Those with a change in the maximum standardised uptake value (∆SUVmax) ≥70% received four further cycles of standard neoadjuvant therapy (PET responder group). PET-predicted poor-responders (∆SUVmax <70%) were randomised (2:1) to receive standard neoadjuvant therapy with (Group A) or without (Group B) bevacizumab for cycles 3-6. All patients received a single cycle of trastuzumab followed by surgery and 11 further cycles of adjuvant trastuzumab, with or without radiotherapy and hormonal therapy if hormone receptor positive cancer. Randomisation was open label using an adaptive minimisation method. Investigators and patients were aware of group assignment. Findings: One hundred and twenty-one patients completed the 5-year follow-up period (PET responder group, n=69; Group A, n=48; Group B, n=25). The 5-year estimated cumulative incidence of recurrence was 9·5% (95% CI: 4·4–20·0%) in PET responders, 9·8% (3·8-24·1%) in Group A, and 24·0% (11·6-45·8%) in Group B. Adding bevacizumab to neoadjuvant therapy increased the proportion of patients experiencing Grade ≥ 3/4 adverse events (Group A: 25·6%; Group B 12·5%) and serious adverse events (Group A: 18·6%; Group B 12·5%), but with no apparent effect on cardiac events. Interpretation: Adding bevacizumab to neoadjuvant docetaxel plus trastuzumab therapy may improve long-term outcomes in women with HER-2-positive breast cancer who are predicted to respond poorly to standard neoadjuvant therapy. Trial Registration: The study is registered with ClinicalTrials.gov (NCT01142778) and EudraCT (2009-013410-26). Funding Statement: Roche France. Declaration of Interests: BC reports personal fees and non-financial support from Roche Laboratories France, personal fees from Bristol Myers Laboratories France, and personal fees from AstraZeneca Laboratories. JYP declares research funding received by his institution from Roche and Menarini Silicon Biosystems; honoraria received by his institution from Roche and Sanofi; and personal fees from Roche, Novartis, AstraZeneca, Pfizer, Amgen, Ipsen, Lilly, and Genomic Health TP is a member of scientific boards for Novartis, Lilly and Pfizer. TB reports personal fees and non-financial support from Roche; grants, personal fees and non-financial support from Novartis, AstraZeneca, and Pfizer; and personal fees from Seattle Genetics, outside the submitted work. DC reports honorarium from Roche, Pfizer, Novartis, Sanofi, and AstraZeneca. GP acted as consultant for Chugai, Novartis and Shire (Takeda), with remunerations received by his institution. GP’s research team received grants for academic studies from Amgen, Genzyme (Sanofi), Lilly, Merck, Novartis, and Roche Pharma. AF and JD are full-time employees of Roche Pharma France. LA reports personal fees and non-financial support from Roche Laboratories France and Bristol Myers Laboratories France, and personal fees from AstraZeneca Laboratories and Merck. M-AM-R, KK, J-MF, FLD, P-FD, PG, M-PC, CB, J-BP, GT, and AB-R declare no conflicts of interest. Ethics Approval Statement: The study was approved by the central Ethics Committee (Comite de Protection des Personnes) for all participating centres and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

A Single-Center, Phase 3, Randomized Controlled Trial of Pancreaticojejunostomy vs Pancreaticogastrostomy with Externalized Stent in High-Risk Pancreatic Anastomosis

Background: Patients at high risk for postoperative pancreatic fistula (POPF) still represent a major concern after pancreaticoduodenectomy (PD). While several meta-analyses of randomized controlled trials (RCTs) have supported pancreaticogastrostomy (PG), other trials have highlighted the superiority of pancreaticojejunostomy (PJ) with externalized transanastomotic stents. This RCT compared PJ to PG, both with externalized transanastomotic stents, specifically in the setting of high POPF risk. Methods: Patients undergoing elective PD were prospectively enrolled. The Fistula Risk Score was intraoperatively calculated to identify patients at high risk for POPF that were subsequently randomized according to a 1:1 allocation. The primary endpoint was POPF. The secondary endpoints were Clavien-Dindo ≥ 3 morbidity, postpancreatectomy hemorrhage (PPH), delayed gastric emptying (DGE) and average complication burden (ACB). Findings: The study lasted from July 2017 to March 2019. A total of 604 patients were screened for eligibility, 82 were at high risk for POPF (FRS 7 - 10), and 72 were randomized to PG (n= 36) or PJ (n= 36). There was no significant difference in the incidence of POPF (50.0 vs. 38.9%, p= 0.477) between PG and PJ, but in the patients who developed a POPF, the ACB was lower for PJ (0.39 vs. 0.25, p= 0.039). Additionally, the rates of PPH (38.9 vs 25.0%, p= 0.312) and DGE (44.4 vs. 50.0%, p= 0.814) were similar, but patients who underwent PG presented a significantly higher incidence of Clavien-Dindo ≥ 3 morbidity (47.2 vs. 22.2%, p= 0.047). Interpretation: In patients at the highest risk for POPF, PG and PJ show similar rates of POPF. However, PG was associated with an increased incidence of Clavien-Dindo ≥ 3 morbidity and with an increased ACB in the patients who developed a POPF. Clinical Trial Registration: NCT03212196 (https://www.clinicaltrial.gov). Funding Statement: This study did not receive any financial support. Declaration of Interests: All other authors declare no competing interests. Ethical Approval Statement: The study protocol was approved by the local ethics committee (Ethics Committee of the provinces of Verona and Rovigo, approval number 1041CESC). The trial was performed in accordance with the good clinical practice guidelines, the principles of the Declaration of Helsinki, and the Consolidated Standards of Reporting Trials (CONSORT) guidelines. All eligible patients provided written informed consent at the time of hospital admission.

Brain networks modeling for studying the mechanism underlying the development of Alzheimer's disease.

Alzheimer's disease is a primary age-related neurodegenerative disorder that can result in impaired cognitive and memory functions. Although connections between changes in brain networks of Alzheimer's disease patients have been established, the mechanisms that drive these alterations remain incompletely understood. This study, which was conducted in 2018 at Northeastern University in China, included data from 97 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset covering genetics, imaging, and clinical data. All participants were divided into two groups: normal control (n = 52; 20 males and 32 females; mean age 73.90 ± 4.72 years) and Alzheimer's disease (n = 45, 23 males and 22 females; mean age 74.85 ± 5.66). To uncover the wiring mechanisms that shaped changes in the topology of human brain networks of Alzheimer's disease patients, we proposed a local naïve Bayes brain network model based on graph theory. Our results showed that the proposed model provided an excellent fit to observe networks in all properties examined, including clustering coefficient, modularity, characteristic path length, network efficiency, betweenness, and degree distribution compared with empirical methods. This proposed model simulated the wiring changes in human brain networks between controls and Alzheimer's disease patients. Our results demonstrate its utility in understanding relationships between brain tissue structure and cognitive or behavioral functions. The ADNI was performed in accordance with the Good Clinical Practice guidelines, US 21CFR Part 50-Protection of Human Subjects, and Part 56-Institutional Review Boards (IRBs)/Research Good Clinical Practice guidelines Institutional Review Boards (IRBs)/Research Ethics Boards (REBs).