tbuckley/cabot-search huggingface dataset:
Outcomes in AML patients age ≥70: A very large single institution experience.
Authors: Jeffrey E. Lancet, Jongphil Kim, Najla Al Ali, Marina Sehovic, Tea Reljic, Benjamin Djulbegovic, Martine Extermann
Journal: Journal of Clinical Oncology (2017)

7031 Background: AML in older adults is associated with poor outcomes. The Moffitt Cancer Center AML Database was used to evaluate a very large cohort of patients (pts) age ≥ 70 with untreated AML to identify key prognostic variables affecting outcome. Methods: Overall survival (OS): Kaplan-Meier method and was compared across groups using the log-rank test. Association between OS and predictors: Cox regression model. Impact of participation of initial clinical trial on OS: Propensity score with stratified log-rank test. A predictive model for 12 month OS was developed using multiple logistic regression with backward elimination method. Results: Nine hundred eighty (980) pts were identified. M/F(%): 66/34. Median age at diagnosis: 75.7 years (range 70 – 95.7 years). De novo/secondary (%): 43/57. Fifty two % of pts had prior hematologic disease (AHD). Baseline karyotype at AML diagnosis: adverse in 31% and non-adverse in 58%. Baseline ECOG PS: 0-1 in 79%; ≥2 in 19%. Median OS was 7.1 months (95% CI 6.4 – 7.9) for the entire cohort. In the univariable model, factors associated with inferior survival included: secondary AML (sAML) status, poor-risk karyotype, ECOG ≥2, non HMA therapy (including clinical trials), Charlson Comorbidity Index ≥3, older age, increased WBC, decreased platelets (plts), and decreased hemoglobin (hgb). Independent negative predictors for OS in the multivariate model included sAML, poor-risk karyotype, ECOG ≥2, non-HMA initial therapy, older age, increased WBC, decreased plts, and decreased hgb. Propensity score matching revealed no significant difference in OS amongst pts receiving initial treatment on a clinical trial (median 7.8 months, 95% CI 6.4 – 10.4) vs not (median 7.0 months, 95% CI 6 –7.9). A model to predict OS at 12 month was developed in a subset of 446 pts. Independent predictive variables included karyotype, ECOG PS, AML type (de novo vs sAML), age, and WBC, with AUC of 0.78, indicating strong discriminatory capacity. Conclusions: In this largest reported cohort of AML pts age ≥ 70, prognostic modeling identifies differences in longer-term survival with conventional therapies, discriminating the highest risk subsets. Decision modeling to further assist choice of optimal therapies for these pts is in progress.
Peripheral Nerve Blocks for Hand Procedures
Authors: Janak Chandrasoma, T. Kyle Harrison, Howard Ching, Lindsey Vokach-Brodsky, Larry F. Chu
Journal: New England Journal of Medicine (2018)

This video shows viewers how to administer a peripheral nerve block. Its primary use, demonstrated here, is to aid the treatment of hand lacerations. This procedure can also be used for other conditions, including dislocations, paronychia, and felon drainage.
Translating Administrative Health Care Data to Treatment Decisions in Dermatology
Authors: Arash Mostaghimi, Adewole S. Adamson
Journal: JAMA Dermatology (2018)

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 Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Dermatology journal
P05.43 Proton therapy of CNS tumors
Authors: P Witt Nyström, K Werlenius, M Blomstrand, M Mudaisi
Journal: Neuro-Oncology (2018)

LGG patients with good prognostic markers and hence an expected long-term survival are in Sweden considered candidates for proton therapy (PT) as an alternative to photon radiotherapy to reduce long-term toxicity. Final decision on treatment modality is made on a national PT board where comparative plans including photon plans are discussed. This is the first report on PT of LGG, WHO grade II, in adults (≥18 years) treated at the Skandion Clinic (SC). It is a national public clinic based on distributed competence, i.e. the patients are prepared for PT at one of the seven university hospitals in Sweden and there after referred to SC which executes the PT, and then re-referred to their home hospital for follow-up. The LGG patients were identified and allocated for RT at regional neuro-oncological multi-disciplinary tumour board. Comparative photon plans were made additionally. The patients were treated with pencil beam scanning PT, with Eclipse (Varian) as treatment planning system. The patients were assessed prospectively for toxicity, and first MRI were performed 3 months after PT. Since clinical start of the SC 36 adult patients with a LGG grade II had been treated and evaluated by MRI 3 months post PT. All had a pathology-verified WHO grade II glioma and treated to a total dose of 50.4–54.0 Gy(RBE). Dominating acute side effects were alopecia, erythema and fatigue grade I-II. At MRI 3 months after PT so far 5 patients have shown a new contrast-enhancing lesion and are under surveillance for progressive disease alternatively pseudo-progression. A comparison between different potential treatment plans showed a large significant reduction of radiation dose to several organs at risk, including brain (>30%). PT of LGG shows a well-tolerated treatment. Noticeable is reports of asymptomatic pseudo-progression on MRI 3 months post treatment.
Germline variant alleles in rs12422149 of <i>SLCO2B1</i> and response to abiraterone acetate (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Andrew W Hahn, David Michael Gill, Peter Hale, Austin Poole, Roberto Nussenzveig, Sara Wilson, James M. Farnham, Robert A Stephenson, Benjamin Louis Maughan, Lisa Cannon-Albright, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2018)

5076 Background: Predictive biomarkers of response to AA in advanced prostate cancer are needed. SLCO2B1 encodes a protein that mediates transport of AA into tissue. A pre-clinical study showed that variant alleles in select single nucleotide polymorphisms (SNPs) for SLCO2B1, rs12422149 and rs1789693, result in higher tumor tissue AA levels (Mostaghel EA, Clin. Can. Res., 28389510). In an exploratory analysis, we found a non-significant trend towards improved progression-free survival (PFS) in men with variant alleles for rs12422149 but not for rs1789693 on AA in mCRPC patients. Here, we interrogate the correlation of variant alleles in rs12422149 with PFS on first-line therapy with AA in men with new mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was PFS on first-line AA in men with mCRPC. We performed a pre-specified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 on PFS on AA. Results: Of 401 men with advanced prostate cancer genotyped. 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03) (Table). Conclusions: In this first clinical validation of pre-clinical data reported by Mostaghel, et al., variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC. These findings need external validation. rs12422149 GG (n=63) rs12422149 AG (n=16) rs12422149 AA (n=0) p value* log PSA at AA Initiation 3.22 (1.47) 3.60 (1.40) NA 0.36 Gleason 0.35 4 2 (3%) 0 0 5-6 4 (6%) 3 (19%) 0 7 14 (22%) 2 (12%) 0 8-10 43 (69%) 11 (69%) 0 Cox Regression results: Median PFS (months) 6.3 8.9 NA Hazard rate 1.0 0.462 (p=0.034) NA HR CIs NA 0.23-0.94 NA *p values are comparisons across the two observed genotypes
A phase I dose escalation study of hPV19, a novel humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in patients with advanced solid tumors refractory to standard therapy.
Authors: Dongmei Ji, Weina Shen, Hongzhen Li, Yan Xia, Yu Wang, Shiping Luo, Qunmin Zhou, Yiqing Xu, Junning Cao
Journal: Journal of Clinical Oncology (2018)

2522 Background: hPV19 is a novel inhibitory mAb against VEGF with unique binding site different from that of Bevacizumab. This phase 1 study aimed to determine its dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety and pharmacokinetics (PK) in patients with advanced solid tumors. Methods: This is a first-in-human study with a 3+3 design. Eligible patients received hPV19 on day 1 and were observed for DLTs for 21 days. Subsequent treatment was every 14 days until disease progression or toxicity. DLTs were defined as occurrence of grade 3 or above non-hematological or grade 4 hematological toxicities. Response was evaluated at week 8 and then every 8 weeks using RECIST criteria. Extension enrollment (n = 5) was planned at dose levels 2.5 mg/kg and 6 mg/kg. Results: From 08/23/2016 to 01/25/2018, 24 patients were enrolled (22 for toxicity study) to 6 dose levels: 0.3 mg/kg (n = 3), 1 mg/kg (n = 3), 2.5 mg/kg (n = 8), 4mg/kg (n = 3), 6mg/kg (n = 4) and 10mg/kg (n = 3, not included in PK or response assessment). The median age was 46.5 years old (range 29-70). No DLTs have been observed and MTD has not been reached. Common grade 3 toxicities were hypertension 22.7%, proteinuria 9%, and LFT abnormalities 9%. Common grade 1 or 2 toxicities were hypertension 13.6%, proteinuria 59%, epistaxis 22.7%, dysphonia 18.2%, LFT abnormality 59%, renal abnormality 27.3%, anemia 22.7%, leukopenia 18.2% and thrombocytopenia 18.2%. A linear AUC dose response with elimination mean serum half-life (t1/2) of 66.88-156.09h (2.78-6.50 days) and Cmax of 4.06 to 132.01μg/ml were observed between doses 0.3 mg/kg to 6 mg/kg. Low titres of anti-hPV19 antibody were detected in 3 patients at 0.3 mg/kg (n = 1) and 1 mg/kg (n = 2). Six patients (27.2%) had clinical response, including 1 PR (breast ca, 2.5mg/kg), and 5 SDs (colon ca x2, renal ca x2 and breast ca x1, at all dose levels). The median duration of response was 27 weeks (range 17-57 weeks). Conclusions: hPV19 is safe and tolerable with promising durable single agent activity in refractory solid tumors. The dose selected for phase Ib /phase II is 4 mg/kg every 2 weeks or 6 mg/kg every 3 weeks. Clinical trial information: CTR20160585.
Redefining the positive margin in pancreatic cancer: Impact of distance on survival.
Authors: Arsen Osipov, Joanne K Rutgers, Deepti Dhall, Jason Naziri, Shefali Chopra, Quanlin Li, Nicholas N. Nissen, Richard Tuli, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2016)

4122 Background: Significant controversy exists regarding prognostic significance of margin clearance and what constitutes a positive margin (R1) in pancreatic ductal adenocarcinoma (PDA). We performed a comprehensive archival analysis of all surgical resection margins (SRM) to determine the effect on locoregional recurrence and survival, and impact of adjuvant therapy in PDA. Methods: We identified 105 patients with resected stage I-III PDA from 2007-2014. SRMs for each patient were identified for pancreatic, anterior, bile duct, and posterior margins (posterior surface, uncinate and vascular groove). Three pathologists reviewed all archival surgical specimens and recategorized each margin as: tumor at ink/transected, < 0.5 mm, 0.5-1 mm, > 1-2 mm or > 2mm from the inked surface. The significance of margins and clinical variables was assessed on disease-free survival (DFS) and overall survival (OS) using multivariate cox proportional hazards modeling. Estimates for DFS and OS were calculated using Kaplan-Meier methods. Results: The pancreatic, anterior and bile duct SRMs were not significant (p > 0.05) predictors of DFS and OS. However, increasing posterior margin clearance up to 2 mm was a significant predictor of DFS (p = 0.001) and OS (p = 0.001). Margin clearance in excess of 2 mm did not impact clinical outcomes DFS (p = 0.08) and OS (p = 0.08). Dichotomizing the posterior SRM at 2 mm revealed it to be an independent predictor of OS (HR 0.31 p = 0.008) and DFS (HR 0.46 p = 0.05) on multivariate analysis (median OS 23.2 [ ≤ 2mm] vs 60 [ > 2mm] months; median DFS 13.9 [ ≤ 2mm] vs 27.3 [ > 2mm] months). Adjusting for multiple covariates, a margin status of > 2mm, was a significant predictor of OS in patients who received adjuvant chemotherapy (ACT) (HR 0.31 p = 0.03), yet this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40 p = 0.19). Conclusions: Among all SRMs in PDA, the posterior margin is the most clinically significant. Achieving SRMs of at least 2 mm has a significant impact on long term clinical outcomes. The addition of radiotherapy to ACT mitigates the negative prognostic significance of a posterior margin less than 2 mm. Comprehensive archival validation in a larger data set may help redefine R1 in PDA.
Inflammatory bowel disease and the risk of prostate cancer.
Authors: Shilajit Kundu, Jacob A Burns, Adam Benjamin Weiner, William Catalona, Edward M. Schaeffer, Ronak Vashi, Eric Li, Stephen Hanauer, Scott Strong, James Burns, Maha Hussain
Journal: Journal of Clinical Oncology (2018)

e17052 Background: Age-specific prostate-specific antigen (PSA) levels and risk of clinically-significant prostate cancer (PCa) are components of shared decision-making for PCa screening. Inflammation is a known cause of elevated PSA values and has been associated with higher rates of PCa. There is limited data on the relationship of inflammatory bowel disease (IBD) with PSA levels and PCa risk. Therefore, we examined screening PSA levels and rates of PCa in patients with IBD compared to age- and race-matched controls. Methods: This retrospective cohort study was conducted from 1996 through 2017 at a single large-scale academic medical center. Male patients with IBD (cases = 1,033) were matched by age and race to men without IBD (controls = 9,306). All patients had undergone at least one screening PSA test. A mixed-effects regression model assessed the association between IBD and PSA level. Chi-square and multivariable logistic regression analyses evaluated the relationship between IBD and cases of any PCa and clinically-significant PCa (Gleason score ≥7). Rates of PCa were also compared per 100,000 person-years of follow-up. Results: Median age of both cases and controls was 59. Beginning at age 60, PSA values were higher among IBD patients (ages 60-64, 1.12 ng/ml for cases vs. 1.04 ng/ml for controls; p = 0.031). The disparity in PSA values between cases and controls increased with age. Risk of any PCa and clinically-significant PCa was higher in patients with IBD (table). This remained true when controlling for covariates (Table). Per 100,000 person-years, the incidence of clinically-significant PCa was 462 cases in IBD patients and 115 cases among controls. Conclusions: In this study, men with IBD had higher PSA levels among those older than 60 and higher rates of clinically-significant PCa overall when compared to age- and race-matched controls. These novel findings warrant future prospective investigation of IBD as a risk factor for PCa. Outcome Odds Ratio (95% CI) p-valuea Any PCa Unadjusted 5.99 (4.24-8.45) < 0.001 Adjustedb 5.53 (3.75-8.16) < 0.001 Clinically-significant PCa Unadjusted 4.97 (3.19-7.72) < 0.001 Adjustedb 4.10 (2.53-6.67) < 0.001 aBy logistic regression bAdjusted for follow-up time, number of office visits, age, race and abnormal rectal exam
Impact of industry funding and collaboration in oncology RCTs.
Authors: Anne Linker, Nitin Roper, Annie Yang, Deborah Korenstein
Journal: Journal of Clinical Oncology (2016)

6592 Background: There is concern that industry involvement may bias randomized trials (RCTs); studies with industry involvement report more positive results and use more surrogate end points. Industry is deeply involved in oncology RCTs; the impact is unclear. We evaluated the association between industry collaboration and funding (ICF) and methodological rigor and results in oncology RCTs. Methods: We searched PubMed for oncology RCTs published from 1/1/10-12/3/15 in journals with impact factor > 5 that require reporting of industry funding and role. We included RCTs evaluating drugs or devices in cancer patients, defining collaboration as industry involvement in study design, analysis, or reporting and positive results as those favoring study drug/device. Trial characteristics and results were extracted by 2 authors. We compared trial characteristics based on funding and collaboration using Fisher exact tests. Results: We included 226 studies from 14 journals; 110 studies had ICF. Compared to non-industry trials (NI), IFCs used better methods; positive results were similar (Table). Conclusions: In oncology RCTs, IFC is associated with methodological rigor and similar rates of positive outcomes compared to NI. Although this study is limited to journals requiring disclosure of the role of the funder, our results suggest that industry involvement in oncology RCTs does not lead to substantial bias. NI (n = 71) Funding only (n = 45) IFC (n = 110 ) No. (%), RR (95% CI) No. (%), RR (95% CI), P Value No. (%), RR (95% CI), P Value ITT 41 (57.7) 23 (51.1), 0.89 (0.62-1.25), 0.57 80 (72.7), 1.26 (1.00-1.58), 0.052 Patient blinding 11 (15.5) 9 (20.0), 1.29 (0.58-2.87), 0.62 48 (43.6), 2.82 (1.57-5.05), < 0.0001 MD blinding 11 (15.5) 9 (20.0), 1.29 (0.58-2.87), 0.62 48 (43.6), 2.82 (1.57-5.05), < 0.0001 Outcome assessor blinding 6 (8.5) 8 (17.8), 2.10 (0.78-5.66), 0.15 36 (32.7), 3.87 (1.72-8.72), 0.00012 1° endpoint : OS 13 (18.3) 10 (22.2), 1.21 (0.58-2.53), 0.64 27 (24.5), 1.34 (0.74-2.42), 0.36 1° endpoint : PFS/DFS 24 (33.8) 18 (40.0), 1.18 (0.72-1.92), 0.55 52 (47.3), 1.40 (0.96-2.05), 0.09 1° endpoint : OR 5 (7.0) 5 (11.1), 1.58 (0.48-5.14), 0.51 9 (8.2), 1.16 (0.41-3.33), 0.99 Positive Result 36 (50.7) 18 (40.0), 0.79 (0.52-1.21), 0.34 65 (60.0), 1.18 (0.90-1.56), 0.22
Outcomes of immune-checkpoint inhibitor induced organ toxicities.
Authors: Hamzah Abu Sbeih, Tenglong Tang, Daniel H. Johnson, Adi Diab, Yinghong Wang
Journal: Journal of Clinical Oncology (2018)

10063 Background: Immune checkpoint inhibitors (ICPIs) are gaining more popularity as treatment for advanced cancers. However, immune-related adverse events (irAE) might limit their use. Immunosuppressants are commonly used to treat irAEs. We aimed to assess the impact of irAEs and their treatment on survival outcomes. Methods: We conducted a retrospective review of patients who received ICPIs between 2011 and 2017, who developed irAEs. Descriptive analyses were used to compare different groups. Kaplan-Meier curves and log rank tests were used to estimate overall survival durations. Results: A total of 427 patients were included in this analyses. IrAEs were observed in 202 patients; single irAE (n = 126), and multiple irAEs (n = 76). ICPI-related diarrhea/colitis was confirmed in 117 patients. Immunosuppressant treatment was needed mainly for grade 2 to 4 diarrhea (83.5%) or grade 2 to 3 colitis (62.0%). Ipilimumab treatment duration was shorter than other ICPIs (P < 0.01). Ipilimumab based regimens were associated with higher risk of irAEs (OR, 2.33; 95% CI, 1.31 – 4.16). Overall, patients developed irAEs had better overall survival than did patients with no irAEs regardless of immunosuppressant treatment (P < 0.01). Patients with mild irAEs who did not need immunosuppressant had better overall survival than did patients without irAEs (P < 0.01). Patients with 3 or more irAEs had better overall survival compared to patients with 2 or less irAEs (P = 0.01). Overall survival of patients who had irAEs that required immunosuppressant was comparable to patients who had irAE that did not require treatment (P = 0.73). Infliximab was associated with shorter duration of steroid use compared to steroid treatment only (2 months [SD, 8] vs. 4 months [SD, 4]). Steroid treatment for more than 30 days was associated with higher rate of infections compared to shorter duration (P = 0.03). Conclusions: IrAEs are associated with a favorable overall survival, regardless of immunosuppression treatment requirement. IrAEs involving multiple organs appeared to be beneficial for overall survival. Early infliximab use shortens the duration of steroid treatment which decreases the risk of steroid-related adverse events.
Phase I/II study of LAG525 ± spartalizumab (PDR001) in patients (pts) with advanced malignancies.
Authors: David S. Hong, Patrick Schoffski, Aitana Calvo, John Sarantopoulos, María Ochoa De Olza, Richard D. Carvajal, Amy Prawira, Chrisann Kyi, Taito Esaki, Wallace L. Akerley, Filippo G. De Braud, Rina Hui, Tian Zhang, Ross A. Soo, Michela Maur, Andrew James Weickhardt, Niladri Roy Chowdhury, Catherine Sabatos-Peyton, Eunice Lee Kwak, Daniel Shao-Weng Tan
Journal: Journal of Clinical Oncology (2018)

3012 Background: LAG525 and spartalizumab (PDR001), humanized IgG4 mAbs, block binding of LAG-3 to MHC class II and PD-1 to PD-L1 and PD-L2, respectively. Preclinical studies show synergistic anti-tumor activity when blocking PD-1 and LAG-3. Here, we report dose escalation results from a Phase I/II study of LAG525 ± spartalizumab in advanced malignancies (NCT02460224). Methods: LAG525 was dosed Q2W (1–15 mg/kg, or 240/400 mg) or Q4W (3–10 mg/kg, or 400 mg); LAG525 + spartalizumab was dosed at 15 dose levels/schedules from 0.3 mg/kg LAG525 + 1 mg/kg spartalizumab Q2W to 1000 mg LAG525 + 400 mg spartalizumab Q4W. Phase I endpoints (dose-limiting toxicities [DLTs], additional safety, pharmacokinetics, efficacy, and biomarkers) were used along with an adaptive Bayesian logistic regression model guided by escalation with overdose control to support future study dosing. Baseline and on-treatment tumor samples were collected. Results: As of 31 Jul 2017, 115/119 pts (97%) receiving LAG525 and 99/121 pts (82%) receiving LAG525 + spartalizumab had discontinued treatment, primarily due to progressive disease (79% and 67%, respectively). DLTs occurred in 4 pts in each arm (LAG525 arm: Gr 3 intra-abdominal fluid collection, lipase increase, vomiting; Gr 4 acute kidney injury. Combination arm: Gr 3 hyperglycemia, pneumonitis, brain tumor edema, fatigue; Gr 4 autoimmune hepatitis) without clear dose relationship. Common (≥10%) related AEs were fatigue (10%) for LAG525 alone and fatigue (18%), diarrhea (15%), and nausea (12%) for the combination. Gr 3–4 related AEs were reported in 10 pts (8%) in the LAG525 arm and 10 pts (8%) in the combination arm. Approximately dose-proportional increases in LAG525 exposure were seen. No MTD was identified for either arm. LAG525 + spartalizumab led to durable RECIST responses (11 PR, 1 CR) in a variety of solid tumors, including mesothelioma (2/8 pts) and triple-negative breast cancer (TNBC; 2/5 pts). In TNBC tumor biopsies, a trend in conversion of immune-cold to immune-activated biomarker profiles was seen. Conclusions: Treatment was well tolerated with preliminary anti-tumor activity and immune profile modulation observed for LAG525 + spartalizumab. Phase II is ongoing in selected indications. Clinical trial information: NCT02460224.