tbuckley/cabot-search huggingface dataset:
Variability in Glycated Hemoglobin and Risk of Poor Outcomes Among People With Type 2 Diabetes in a Large Primary Care Cohort Study
Authors: Julia A. Critchley, Iain M. Carey, Tess Harris, Stephen DeWilde, Derek G. Cook
Journal: Diabetes Care (2019)

Diabetes guidelines focus on target glycated hemoglobin (HbA1c) levels. Long-term variability in HbA1c may be predictive of hospitalization or mortality, but its importance at different average levels or trajectories is unclear.Using English primary care data, 58,832 patients with type 2 diabetes had HbA1c average (mean of annual means), variability (coefficient of variation), and trajectory (annual regression slope) estimated during 2006-2009. Hazard ratios (HRs) for mortality and emergency hospitalization during 2010-2015, with adjustment for age, sex, smoking, BMI, duration of diabetes, and deprivation, were estimated using Cox regression. The simultaneous impact of HbA1c average, variability, and trajectory was estimated using percentiles.In mutually adjusted models, HbA1c variability showed a consistent dose-response relationship with all-cause mortality, while average level was only important among individuals in the highest or lowest 10% of the distribution, and trajectory had no independent effect. Individuals with the most unstable HbA1c (top 10%) were almost twice as likely to die (HR 1.93 [95% CI 1.72-2.16]) than were those with the most stable (bottom 10%)-an association attenuated but not explained by hypoglycemia. For emergency hospitalizations, similar trends were seen except for coronary artery disease (CAD) and ischemic stroke (IS), where increasing average rather than variability was predictive.HbA1c variability was strongly associated with overall mortality and emergency hospitalization and not explained by average HbA1c or hypoglycemic episodes. Only for CAD and IS hospitalizations was no association found, with average HbA1c strongly predictive. Targets should focus on both stability and absolute level of HbA1c.
Abstract 12186: Therapeutic Effects of Blockade of IL-6/gp130 Signaling in Pulmonary Arterial Hypertension
Authors: Yuichi Tamura, Carole Phan, Ly Tu, Raphaël Thuillet, Morane Le Hiress, Alice Huertas, Elie Fadel, Gerald Simonneau, Marc Humbert, Christophe Guignabert
Journal: Circulation (2015)

Background: Interleukin (IL)-6 has been linked to the prognosis of pulmonary arterial hypertension (PAH). However, precise contributions of IL-6 and its signaling system to PAH progression is still obscure. Objectives: To study pathogenic roles of IL-6 cis- and trans-signaling in experimental and human PAH and to evaluate the translational potential of IL-6 signaling inhibition. Methods: We examined the global expression pattern of key actors of the IL-6 signaling in human lung tissues, blood samples and cultured pulmonary artery-smooth muscle cells (PA-SMCs) of 10 controls and 10 idiopathic PAH (IPAH) patients. In addition, two complementary animal models of pulmonary hypertension (PH) have been studied: the monocrotaline and SU5416 plus chronic hypoxia rat models. Results: In IPAH, serum levels of IL-6 and soluble IL-6 receptors (sIL-6R) proteins were higher than in control subjects. We also found stronger immunoreactivity for IL-6R, p-STAT3 and myeloid leukemia-cell protein 1 (Mcl-1, a downstream target of IL-6) in the media of remodeled pulmonary arteries and cultured PA-SMCs of IPAH patients compared with controls. These abnormalities in the IL-6/IL-6R signaling were also histologically found in the two rat models. Consistent with these findings, we also found that IL-6 with or without sIL-6R could substantially increase p-STAT3 and the anti-apoptotic Mcl-1 protein in cultured IPAH PA-SMCs compared with control cells. These effects were totally abolished in the presence of IL-6R neutralizing antibodies and an IL-6R antagonist. Finally, we found that daily treatment with IL-6R antagonist started 1 week after a subcutaneous monocrotaline injection substantially attenuates the abnormal increase in p-STAT3 and Mcl-1 and regresses established PH. Conclusions: We demonstrate here that anti-IL-6R strategies may represent promising novels anti-proliferative and anti-inflammatory approaches for treatment of PAH.
Efficacy and safety of anlotinib in advanced leiomyosarcoma: Subgroup analysis of a phase IIB trial (ALTER0203)
Authors: Y. Chi, Y. Yao, Z. Fang, S. Wang, G. Huang, Q. Cai, G. Shang, G. Wang, G. Qu, Q. Wu, Y. Jiang, J. Song, J. Chen, X. Zhu, Z. Cai, C. Bai, Y. Lu, Z. Yu, J. Shen, J. Cai
Journal: Annals of Oncology (2019)
Combined inhibition of Cdk9 and AKT induces apoptosis of metastatic prostate cancer cells
Authors: Subhra Mohapatra, Baoky Chu, Xiuhua Zhao, Jin Cheng, W. Pledger
Journal: Cancer Research (2007)

5399  Prostate cancer (PCa) is one of the most common malignancies in humans and the second leading cause of male cancer death in America. Prostate cancer mortality results from metastases to bones and lymph nodes and progression from androgen-dependent to androgen-independent disease. Therapeutics for these aggressive forms of cancers are lacking. Previously, we reported that the cyclin dependent kinase inhibitor (CDK) roscovitine down-regulates the expression of X-linked Inhibitor of Apoptosis (XIAP) in metastatic PCas and can induce cell death of PCas that express functional p53. In this study, we found that roscovitine can inhibit cell growth, reduce colony formation and induce apoptosis in PC3 and PC3-M cells that are p53 negative, when co-cultured with either LY294002 (LY) or Triciribine (also known as small molecular Akt/Protein Kinase B signaling Inhibitor-2 (API-2)), which are inhibitors of Akt. Neither roscovitine nor LY or API-2 by itself is sufficient to induce apoptosis of these tumor cells. Further, apoptosis induced by the combination treatment was inhibited by pre-treatment of PC3 cells with a pan-caspase inhibitor and caspase-3 and -9 inhibitors, but not a caspase-8 inhibitor, suggesting that the combination induce the mitochondrial pathway of apoptosis. However, the above combination treatment, when added to RWPE cells for 20 hours, had very little effect, suggesting that the combination treatment is not toxic to normal prostate epithelial cells. In PC3 cells, roscovitine reduced abundance of XIAP but not Mcl-1, whereas API-2 induced Bim. The effect of roscovitine was mimicked by depletion of Cdk9, but not Cdk7 by RNA interference. Moreover, depletion of XIAP or Cdk9 by RNA interference was sufficient to sensitize PC3 and PC-3M cells towards API-2 and induce apoptosis. Collectively, these studies suggest that combined inhibition of Cdk9 and Akt can be effective in treating metastatic prostate cancer in the future.
Multicenter phase I/II feasibility study of adjuvant treatment with S-1 in patients after R0-resection of adenocarcinoma of the stomach and esophagogastric junction (GMBH-STO-0114)
Authors: K. Heinrich, V. Heinemann, L. Müller, P. Büchner-Steudel, T.J. Ettrich, S. Stintzing, C. Schulz
Journal: Annals of Oncology (2019)
Subconcussive Football Hits May Leave a Telltale Signature of Brain Damage
Authors: Feyza Sancar
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Predictors and impacts of second-line chemotherapy on survival after progression in patients with advanced non-small cell lung cancer (NSCLC)
Authors: S. Teramukai, T. Nishimura, M. Nakagawa, M. Kawahara, K. Kubota, K. Furuse, M. Fukushima
Journal: Journal of Clinical Oncology (2007)

7675 Background: Survival after progression (SAP) was longer (median: 8 months) than progression-free survival (median: 6 months) in a phase III randomized trial in patients with stage IIIB or IV NSCLC (SWOG-Japan Common Arm Trial, the Japan Multinational Trial Organization LC00–03, Kawahara, PASCO 2006, #7013). The overall survival in the trial was longer than that in the US populations (median: 14 months vs. 9 months in the paclitaxel/carboplatin arms, Crowley, PASCO 2006, #7050). The aims of this study were to identify predictors and to assess impacts of second-line chemotherapy on SAP of advanced NSCLC. Methods: To identify independent predictors and to estimate hazard ratios (HR) for SAP, we used the Cox proportional hazards model. We evaluated survival benefit of second-line chemotherapies after adjustment for baseline factors and regimens of first-line therapy, types of progression, and time to progression. Results: Out of 393 patients in the LC00–03 trial, 340 patients had progressive disease during the follow-up period. The identified independent significant predictors for SAP were PS (HR: 2.19, p&lt;0.001), weight loss (HR: 1.48, p=0.020), smoking (HR: 1.36, p=0.025), and LDH (HR: 1.37, p=0.032) as baseline factors. Lymph node metastases (HR: 2.17, p&lt;0.001) and bone metastases (HR: 1.75, p=0.004) were poor predictors and relapse in primary lesion was a good predictor (HR: 0.74, p=0.027). Time to progression was correlated with SAP (p=0.008). The median SAP according to second-line treatments were 13 months in gefitinib treatment (response rate: 23%, n=67) and 9 months in other chemotherapies (n=174). The difference is not statistically significant after adjustment for the confounding factors (HR: 0.96, 95%CI: 0.65–1.41), although gefitinib was used after third-line at a constant proportion. Conclusions: Our study shows that baseline factors (PS, weight loss, smoking, LDH) and types of metastases at progression (lymph node, bone) are important prognostic factors for SAP, suggesting minimal effect of selecting gefitinib as a second-line treatment on SAP. [Table: see text]
A phase Ib/ II trial to assess the safety and efficacy of CXD101 in combination with the PD-1 inhibitor nivolumab in patients with metastatic, previously-treated, microsatellite-stable (MSS) colorectal carcinoma (short title CAROSELL)
Authors: M.P. Saunders, J. Graham, D. Cunningham, R. Plummer, S. Cook, D. Church, R. Kerr, N La Thangue, D.J. Kerr
Journal: Annals of Oncology (2019)
A phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: J. Bendell, C. Lieu, K.P.S. Raghav, G. Argilés, A. Cubillo, X. Qu, Y. Yan, M. Merchant, H. Zeuner, J.D. Gallo, N.H. Segal
Journal: Annals of Oncology (2019)
PIK3CA alterations in metastatic breast cancer (mBC)
Authors: J. Albanell, D. Casadevall, E.S. Sokol, L.A. Albacker, J.A. Elvin, J.-A. Vergilio, J.K. Killian, N. Ngo, D. Lin, S. Ramkissoon, E. Severson, S.M. Ali, A.B. Schrock, J. Chung, P. Reddy, V.A. Miller, B.M. Alexander, K. McGregor, J.S. Ross, B. Leyland-Jones
Journal: Annals of Oncology (2019)
Baseline quality of life (QoL) and chemotherapy related toxicities (CRT) in localized breast cancer (BC) patients (pts): The French multicentric prospective CANTO cohort study
Authors: I. Licaj, S. Dabakuyo, S. Dauchy, I. Vaz Luis, C. Charles, C. Lemogne, O. Tredan, L. Vanlemmens, C. Jouannaud, C. Levy, O. Rigal, M. Fournier, T. Petit, F. Dalenc, P. Rouanet, A. Arnaud, J. Lemonnier, S. Everhard, P.H. Cottu, F. Joly
Journal: Annals of Oncology (2019)
Bringing Oncohistones into the Fold
Authors: Jay F. Sarthy, Steven Henikoff
Journal: Cancer Discovery (2019)

Abstract Summary: Identification of cancer-associated mutations in core histone genes has proved challenging due to these genes' highly conserved nature and presence in large arrays. Recent analyses of cancer genomes, including one in this issue of Cancer Discovery, show that mutations in the histone fold can affect nucleosome stability, providing a novel mechanism by which oncohistones contribute to tumorigenesis. See related article by Bennett et al., p. 1438.
Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on the experimental thoracic radiotherapy (TRT) arms of CALGB 30610 (Alliance) / RTOG 0538
Authors: J. Bogart, X. Wang, G. Masters, H. Zhu, R. Komaki, L. Gaspar, M.C. Dobelbower, C. Kuzma, J. Heymach, E.E. Vokes, T. Stinchcombe
Journal: Annals of Oncology (2019)
National Update on Measles Cases and Outbreaks — United States, January 1–October 1, 2019
Authors: Manisha Patel, Adria D. Lee, Nakia S. Clemmons, Susan B. Redd, Sarah Poser, Debra Blog, Jane R. Zucker, Jessica Leung, Ruth Link-Gelles, Huong Pham, Robert J. Arciuolo, Elizabeth Rausch-Phung, Bettina Bankamp, Paul A. Rota, Cindy M. Weinbaum, Paul A. Gastañaduy
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

During January 1-October 1, 2019, a total of 1,249 measles cases and 22 measles outbreaks were reported in the United States. This represents the most U.S. cases reported in a single year since 1992 (1), and the second highest number of reported outbreaks annually since measles was declared eliminated* in the United States in 2000 (2). Measles is an acute febrile rash illness with an attack rate of approximately 90% in susceptible household contacts (3). Domestic outbreaks can occur when travelers contract measles outside the United States and subsequently transmit infection to unvaccinated persons they expose in the United States. Among the 1,249 measles cases reported in 2019, 1,163 (93%) were associated with the 22 outbreaks, 1,107 (89%) were in patients who were unvaccinated or had an unknown vaccination status, and 119 (10%) measles patients were hospitalized. Closely related outbreaks in New York City (NYC) and New York State (NYS; excluding NYC), with ongoing transmission for nearly 1 year in large and close-knit Orthodox Jewish communities, accounted for 934 (75%) cases during 2019 and threatened the elimination status of measles in the United States. Robust responses in NYC and NYS were effective in controlling transmission before the 1-year mark; however, continued vigilance for additional cases within these communities is essential to determine whether elimination has been sustained. Collaboration between public health authorities and undervaccinated communities is important for preventing outbreaks and limiting transmission. The combination of maintenance of high national vaccination coverage with measles, mumps, and rubella vaccine (MMR) and rapid implementation of measles control measures remains the cornerstone for preventing widespread measles transmission (4).
Safety and efficacy of CDX-014, an antibody-drug conjugate against T Cell immunoglobulin mucin-1 (TIM-1), in advanced renal cell carcinoma
Authors: B.A. McGregor, N. Agarwal, M. Gordon, S. George, D.I. Quinn, M. Rogalski, T. Keler, T. Hawthorne, T.K. Choueiri
Journal: Annals of Oncology (2019)
Characterization of a novel BBB-permeable mutant IDH1 inhibitor, DS-1001b
Authors: H. Matsunaga, Y. Machida, M. Nakagawa, M. Yamaguchi, Y. Ogawara, Y. Shima, K. Yamagata, T. Katsumoto, A. Hattori, M. Itoh, T. Seki, Y. Nishiya, K. Nakamura, K. Suzuki, T. Imaoka, M. Suzuki, O. Sampetrean, H. Saya, K. Ichimura, I. Kitabayashi
Journal: Annals of Oncology (2019)
Validation of a Frailty Score Predicting Survival of Elderly, Non-Fit AML Patients Receiving Hypomethylating Therapy: Results of the Decider Trial
Authors: Valerie Hupfer, Olga Grishina, Claudia Schmoor, Richard F. Schlenk, Helmut R. Salih, Martina Crysandt, Michael Heuser, Hans-Walter Lindemann, Carsten Müller-Tidow, Gesine Bug, Ulrich Germing, Katharina S. Götze, Carsten Schwänen, Sebastian Scholl, Aristoteles Giagounidis, Andreas Neubauer, Jürgen Krauter, Arnold Ganser, Hartmut Döhner, Björn Hackanson, Gabriele Ihorst, Michael Lubbert
Journal: Blood (2018)
Targeting molecular mediators of T cell exclusion for effective immunotherapy in ovarian cancer
Authors: Y. Wang, M. Desbois, A. Udyavar, L. Ryner, C. Kozlowski, Y. Guan, M. Dürrbaum, S. Lu, J.-P. Fortin, H. Koeppen, J. Ziai, C.-W. Chang, A. Lo, S. Keerthivasan, M. Plante, C. Bais, P. Hegde, A. Daemen, S. Turley
Journal: Annals of Oncology (2019)
5-year survival outcomes of the CheckMate 067 phase III trial of nivolumab plus ipilimumab (NIVO+IPI) combination therapy in advanced melanoma
Authors: J.M.G. Larkin, V. Chiarion-Sileni, R. Gonzalez, J.J. Grob, P. Rutkowski, C. Lao, C.L. Cowey, D. Schadendorf, J. Wagstaff, R. Dummer, P.F. Ferrucci, M. Smylie, D. Hogg, A. Hill, I. Marquez-Rodas, J B A G Haanen, J. Rizzo, A. Balogh, F.S. Hodi, J. Wolchok
Journal: Annals of Oncology (2019)
The prognostic nutritional index (PNI) is an independent predictor of survival in advanced biliary cancers (ABC) receiving first-line chemotherapy (1L)
Authors: F. Caputo, M. Salati, K. Cerma, A. Spallanzani, K. Andrikou, F. Gelsomino, G. Orsi, G. Rovesti, M.L. Riggi, E. Molinaro, C. Santini, C. Bardasi, M. Rimini, S. Pipitone, G. Cortesi, F.M. Schipilliti, F. Canino, A. Casadei-gardini, S. Cascinu
Journal: Annals of Oncology (2019)
Molecular characteristics in lung squamous cell carcinomas dependent on TP53 status: Putative targets
Authors: V.D. Haakensen, A. Khadse, V. Sandhu-Baveja, A.R. Halvorsen, L.H. Jørgensen, S. Solberg, O.T. Brustugun, E. Kure, A. Helland
Journal: Annals of Oncology (2019)
Deep learning-based classification of mesothelioma improves prediction of patient outcome
Authors: Pierre Courtiol, Charles Maussion, Matahi Moarii, Elodie Pronier, Samuel Pilcer, Meriem Sefta, Pierre Manceron, Sylvain Toldo, Mikhail Zaslavskiy, Nolwenn Le Stang, Nicolas Girard, Olivier Elemento, Andrew G. Nicholson, Jean-Yves Blay, Françoise Galateau-Sallé, Gilles Wainrib, Thomas Clozel
Journal: Nature Medicine (2019)
Are Conditioned Open Placebos Feasible as an Adjunctive Treatment to Opioids? Results from a Single-Group Dose-Extender Pilot Study with Acute Pain Patients
Authors: Michael H. Bernstein, Molly Magill, Arnold-Peter Weiss, Ted J. Kaptchuk, Charlotte Blease, Irving Kirsch, Josiah D. Rich, Sara J. Becker, Steven Mach, Francesca L. Beaudoin
Journal: Psychotherapy and Psychosomatics (2019)
Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial
Authors: John H Beigel, Evgenia Aga, Marie-Carmelle Elie-Turenne, Josalyn Cho, Pablo Tebas, Carol L Clark, Jordan P Metcalf, Caroline Ozment, Kanakatte Raviprakash, Joy Beeler, H Preston Holley, Stephanie Warner, Carla Chorley, H Clifford Lane, Michael D Hughes, Richard T Davey, John H Beigel, Evgenia Aga, Marie-Carmelle Elie-Turenne, Josalyn Cho, Pablo Tebas, Carol L Clark, Jordan P Metcalf, Caroline Ozment, Kanakatte Raviprakash, Joy Beeler, H. Preston Holley, Stephanie Warner, Carla Chorley, H. Clifford Lane, Michael D Hughes, Richard T Davey, Michelle Barron, Aveh Bastani, Philippe Bauer, William Borkowsky, Charles Cairns, Jaime Deville, Marie-Carmelle Elie, Carl Fichtenbaum, Robert Finberg, Mamta Jain, David Kaufman, Michael Lin, John Lin, Ryan Maves, Lee Morrow, Minh-Hong Nguyen, Pauline Park, Christopher Polk, Adrienne Randolph, Suchitra Rao, Lewis Rubinson, Christina Schofield, Shmuel Shoham, Erika Stalets, Renee D Stapleton
Journal: The Lancet Respiratory Medicine (2019)
High prevalence of cannabis use among patients with hidradenitis suppurativa: results from the VERADDICT survey
Authors: C. Lesort, A.P. Villani, J. Giai, P.A. Becherel, J. Delaunay, K. Fattouh, E. Ducroux, D. Jullien, P. Guillem
Journal: British Journal of Dermatology (2019)
Effect on Treatment Adherence of Distributing Essential Medicines at No Charge
Authors: Navindra Persaud, Michael Bedard, Andrew S. Boozary, Richard H. Glazier, Tara Gomes, Stephen W. Hwang, Peter Jüni, Michael R. Law, Muhammad M. Mamdani, Braden J. Manns, Danielle Martin, Steven G. Morgan, Paul I. Oh, Andrew D. Pinto, Baiju R. Shah, Frank Sullivan, Norman Umali, Kevin E. Thorpe, Karen Tu, Andreas Laupacis
Journal: JAMA Internal Medicine (2019)

<h3>Importance</h3> Nonadherence to treatment with medicines is common globally, even for life-saving treatments. Cost is one important barrier to access, and only some jurisdictions provide medicines at no charge to patients. <h3>Objective</h3> To determine whether providing essential medicines at no charge to outpatients who reported not being able to afford medicines improves adherence. <h3>Design, Setting, and Participants</h3> A multicenter, unblinded, parallel, 2-group, superiority, outcomes assessor–blinded, individually randomized clinical trial conducted at 9 primary care sites in Ontario, Canada, enrolled 786 patients between June 1, 2016, and April 28, 2017, who reported cost-related nonadherence. Follow-up occurred at 12 months. The primary analysis was performed using an intention-to-treat principle. <h3>Interventions</h3> Patients were randomly allocated to receive free medicines on a list of essential medicines in addition to otherwise usual care (n = 395) or usual medicine access and usual care (n = 391). <h3>Main Outcomes and Measures</h3> The primary outcome was adherence to treatment with all medicines that were appropriately prescribed for 1 year. Secondary outcomes were hemoglobin A<sub>1c</sub>level, blood pressure, and low-density lipoprotein cholesterol levels 1 year after randomization in participants taking corresponding medicines. <h3>Results</h3> Among the 786 participants analyzed (439 women and 347 men; mean [SD] age, 51.7 [14.3] years), 764 completed the trial. Adherence to treatment with all medicines was higher in those randomized to receive free distribution (151 of 395 [38.2%]) compared with usual access (104 of 391 [26.6%]; difference, 11.6%; 95% CI, 4.9%-18.4%). Control of type 1 and 2 diabetes was not significantly improved by free distribution (hemoglobin A<sub>1c</sub>, −0.38%; 95% CI, −0.76% to 0.00%), systolic blood pressure was reduced (−7.2 mm Hg; 95% CI, −11.7 to −2.8 mm Hg), and low-density lipoprotein cholesterol levels were not affected (−2.3 mg/dL; 95% CI, −14.7 to 10.0 mg/dL). <h3>Conclusions and Relevance</h3> The distribution of essential medicines at no charge for 1 year increased adherence to treatment with medicines and improved some, but not other, disease-specific surrogate health outcomes. These findings could help inform changes to medicine access policies such as publicly funding essential medicines. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT02744963