Utility of human epididymis protein 4 in the differential diagnosis of ascites.

BACKGROUND AND AIMS: Human epididymal protein 4 (HE4) may be a useful tool in the differential diagnosis of malignant ascites. The aim of this study was to evaluate the diagnostic utility of HE4 for detecting malignant ascites, taking into account the possible false positives identified with adenosine deaminase (ADA), C-reactive protein (CRP), % polynuclear cells (%PMN) and glomerular filtration rate (eGFR). METHODS: Concentrations of HE4, ADA, %PMN and CRP were determined in 114 samples of peritoneal fluid and creatinine in serum in order to calculate eGFR. RESULTS: Concentrations of HE4 presented significant differences (P = 0.028) in benign [median (interquartile range)] [582(372)] pmol/L) and malignant ascites ([8241(367)] pmol/L. Sensitivity was 21.2% and specificity 100%. Significant differences were also observed for HE4 between tumors of gynecological origin ([3165(8769)] pmol/L) and others ([665(663)] pmol/L), with a sensitivity of 67% and a specificity of 100%. Classifying according to possible false positives (ADA > 45U/L, CRP > 50 mg/L, %PMN > 90 and eGFR < 30 mL/min/1.73 m2) at maximum specificity, a sensitivity of 33.3% was obtained for HE4, with a cut-off point of 2660 pmol/L. Without possible false positives (ADA < 45U/L, CRP < 50 mg/L, %PMN < 90 and eGFR ≥ 30 mL/min/1.73 m2), a sensitivity of 37.7% was obtained at 100% specificity for a cut-off point of 1041 pmol/L. Applying these criteria to the entire group, a sensitivity of 36.4% was obtained at maximum specificity. CONCLUSIONS: HE4 allows the identification of malignant ascites with moderate sensitivity at maximum specificity. HE4 levels can differentiate between tumors of gynecological origin and others. Classification according to possible false positives increases sensitivity without losing specificity.

Factors associated with lesion detection in colonoscopy among different indications.

BACKGROUND AND OBJECTIVE: Different factors may influence colonoscopy performance measures. We aimed to analyze procedure- and endoscopist-related factors associated with detection of colorectal lesions and whether these factors have a similar influence in the context of different colonoscopy indications: positive fecal immunochemical test (+FIT) and post-polypectomy surveillance colonoscopies. METHODS: This multicenter cross-sectional study included adults aged 40-80 years. Endoscopists (N = 96) who had performed ≥50 examinations were assessed for physician-related factors. Adenoma detection rate (ADR), adenomas per colonoscopy rate (APCR), advanced ADR, serrated polyp detection (SDR), and serrated polyps per colonoscopy rate (SPPCR) were calculated. RESULTS: We included 12,932 procedures, with 4810 carried out after a positive FIT and 1967 for surveillance. Of the 96 endoscopists evaluated, 43.8% were women, and the mean age was 41.9 years. The ADR, advanced ADR, and SDR were 39.7%, 17.7%, and 12.8%, respectively. Adenoma detection rate was higher in colonoscopies after a +FIT (50.3%) with a more than doubled advanced ADR compared to non-FIT procedures (27.6% vs. 13.0%) and similar results in serrated lesions (14.7% vs. 13.5%). Among all the detection indicators analyzed, withdrawal time was the only factor independently related to improvement (p < 0.001). Regarding FIT-positive and surveillance procedures, for both indications, withdrawal time was also the only factor associated with a higher detection of adenomas and serrated polyps (p < 0.001). Endoscopist-related factors (i.e., weekly hours dedicated to endoscopy, annual colonoscopy volume and lifetime number of colonoscopies performed) had also impact on lesion detection (APCR, advanced ADR and SPPCR). CONCLUSIONS: Withdrawal time was the factor most commonly associated with improved detection of colonic lesions globally and in endoscopies for + FIT and post-polypectomy surveillance. Physician-related factors may help to address strategies to support training and service provision. Our results can be used for establishing future benchmarking and quality improvement in different colonoscopy indications.

Prevalence of missed lesions in patients with inadequate bowel preparation through a very early repeat colonoscopy.

OBJECTIVES: When bowel preparation (BP) is inadequate, international guidelines recommend repeating the colonoscopy within 1 year to avoid missing clinically relevant lesions. We aimed to determine the rate of missed lesions in patients with inadequate BP through a very early repeat colonoscopy with adequate BP. METHODS: Post hoc analysis was conducted using data collected from a prospective multicenter randomized clinical trial including patients with inadequate BP and then repeat colonoscopy. Inadequate BP was defined as the Boston Bowel Preparation Scale (BBPS) score <2 points in any segment. We included patients with any indication for colonoscopy. The adenoma detection rate (ADR), advanced ADR (AADR), and serrated polyp detection rate (SPDR) were calculated for index and repeat colonoscopies. RESULTS: Of the 651 patients with inadequate BP from the original trial, 413 (63.4%) achieved adequate BP on repeat colonoscopy. The median interval between index and repeat colonoscopies was 28 days. On repeat colonoscopy, the ADR was 45.3% (95% confidence interval [CI] 40.5-50.1%), the AADR was 10.9% (95% CI 8.1-14.3%), and the SPDR was 14.3% (95% CI 10.9-17.7%). Cancer was discovered in four patients (1%; 95% CI 0.2-2.5%). A total of 60.2% of all advanced adenoma (AA) were discovered on repeat colonoscopy. A colon segment scored BBPS = 0 had most AA (66.1%) and all four cancers. CONCLUSION: Patients with inadequate BP present a high rate of AAs on repeat colonoscopy. When a colonoscopy has a colon segment score BBPS = 0, we recommend repeating the colonoscopy as soon as possible.

1L NER1006 can improve rates of adequate and high-quality bowel cleansing in the right colon: a post hoc analysis of two randomised clinical trials.

BACKGROUND: The right colon is difficult to cleanse compared with other colon segments. This post hoc analysis of two randomised clinical trials (MORA and NOCT) examined whether 1L polyethylene glycol (PEG) NER1006 and two mid-volume alternatives could improve adequate and high-quality cleansing in the right colon among patients with complete cleansing assessments. METHODS: Patients received NER1006 (N2D), 2L PEG plus ascorbate (2LPEG) or oral sulphate solution (OSS) as a 2-day evening/morning split-dosing regimen or NER1006 as a same-day morning-only dosing regimen (N1D). Patients had full segmental scoring assigned by treatment-blinded central readers using the Harefield Cleansing Scale. The right colon adequate (score ≥ 2) and high-quality (score ≥ 3) cleansing success of NER1006 (N2D and N1D) versus 2LPEG and OSS was analysed individually and as pooled groups (N2D vs. 2LPEG/OSS). We assessed the comparative right colon cleansing rates of the N2D versus 2LPEG/OSS in overweight males. We also performed a multivariable regression analysis to examine factors affecting cleansing in the right colon. RESULTS: A total of 1307 patients were included. Pooled N2D showed significantly improved rates of adequate-level cleansing in the right colon compared with 2LPEG (97.5% [504/517] vs. 94.6% [246/260]; p = 0.020) and OSS (97.5% [504/517] vs. 93.8% [244/260]; p = 0.006). In MORA, the rate of adequate right colon cleansing did not significantly differ between N1D and 2LPEG (95.2% [257/270] vs. 94.6% [246/260]; p = 0.383). The rate of right colon high-quality cleansing was significantly improved with N2D or N1D vs. 2LPEG (p < 0.001 for both), and was numerically higher with N2D versus OSS (p = 0.11). In overweight males, NER1006 delivered numerically higher adequate (p = 0.398) and superior high-quality (p = 0.024) cleansing rates versus 2LPEG/OSS. Multivariable regression analysis showed NER1006 was associated with adequate and high-quality cleansing (p = 0.031 and p < 0.001), while time between preparation and colonoscopy was negatively associated (p = 0.034 and p = 0.006). CONCLUSIONS: NER1006 delivered improved rates of adequate and high-quality right colon cleansing compared with 2LPEG and OSS. The increased rate of high-quality cleansing with NER1006 versus its comparators was also seen in overweight males.

Location, morphology and invasiveness of lateral spreading tumors in the colorectum differ between two large cohorts from an eastern and western country.

BACKGROUND AND STUDY AIMS: Data from Japanese series show that surface morphology of laterally spreading tumors (LST) in the colon identifies lesions with different incidence and pattern of submucosal invasion. Such data from western countries are scarce. We compared clinical and histological features of LST in a western country and an eastern country, with special interest on mucosal invasiveness of LST, and investigated the effect of clinical factors on invasiveness in both countries. PATIENTS AND METHODS: Patients with LST lesions ≥20mm were included from a multicenter prospective registry in Spain and from a retrospective registry from the National Cancer Center Hospital East, Japan. The primary outcome was the presence of submucosal invasion in LST. The secondary outcome was the presence of high-risk histology, defined as high-grade dysplasia or submucosal invasion. RESULTS: We evaluated 1102 patients in Spain and 663 in Japan. Morphological and histological characteristics differed. The prevalence of submucosal invasion in Japan was six-fold the prevalence in Spain (Prevalence Ratio PR=5.66; 95%CI: 3.96, 8.08), and the prevalence of high-risk histology was 1.5 higher (PR=1.44; 95%CI: 1.31, 1.58). Compared to the granular homogeneous type and adjusted by clinical features, granular mixed, flat elevated, and pseudo-depressed types were associated with higher odds of submucosal invasion in Japan, whereas only the pseudo-depressed type showed higher risk in Spain. Regarding high-risk histology, both granular mixed and pseudo-depressed were associated with higher odds in Japan, compared with only the granular mixed type in Spain. CONCLUSION: This study reveals differences in location, morphology and invasiveness of LST in an eastern and a western cohort.

The Answer to "When to Clip" After Colorectal Endoscopic Mucosal Resection Based on a Cost-Effectiveness Analysis.

INTRODUCTION: Delayed bleeding (DB) is the most common major complication of endoscopic mucosal resection (EMR). Two randomized clinical trials recently demonstrated that clip closure after EMR of large nonpedunculated colorectal polyps (LNPCPs) reduces the risk of DB. We analyzed the cost-effectiveness of this prophylactic measure. METHODS: EMRs of LNCPCPs were consecutively registered in the ongoing prospective multicenter database of the Spanish EMR Group from May 2013 until July 2017. Patients were classified according to the Spanish Endoscopy Society EMR group (GSEED-RE2) DB risk score. Cost-effectiveness analysis was performed for both Spanish and US economic contexts. The average incremental cost-effectiveness ratio (ICER) thresholds were set at 54,000 € or $100,000 per quality-adjusted life year, respectively. RESULTS: We registered 2,263 EMRs in 2,130 patients. Applying their respective DB relative risk reductions after clip closure (51% and 59%), the DB rate decreased from 4.5% to 2.2% in the total cohort and from 13.7% to 5.7% in the high risk of the DB GSEED-RE2 subgroup. The ICERs for the universal clipping strategy in Spain and the United States, 469,706 € and $1,258,641, respectively, were not cost effective. By contrast, selective clipping in the high-risk of DB GSEED-RE2 subgroup was cost saving, with a negative ICER of -2,194 € in the Spanish context and cost effective with an ICER of $87,796 in the United States. DISCUSSION: Clip closure after EMR of large colorectal lesions is cost effective in patients with a high risk of bleeding. The GSEED-RE2 DB risk score may be a useful tool to identify that high-risk population.

Colonic stent vs surgical resection of the primary tumor. Effect on survival from stage-IV obstructive colorectal cancer.

BACKGROUND AND OBJECTIVES: the impact of surgical primary tumor resection on survival of obstructive metastatic colorectal cancer remains controversial. The primary goal of this study was to analyze survival in patients with obstructive metastatic colorectal cancer after treatment with either resection surgery or a colonic stent. MATERIAL AND METHODS: a prospective study was performed of all patients with stage-IV colorectal cancer and obstructive manifestations, diagnosed from 2005 to 2012 and managed with either resection surgery or a colonic stent. Cases with a perforation, abscess, right colon or distal rectal malignancy, multiple colorectal cancer or derivative surgery were excluded. RESULTS: a total of 95 patients were included, 49 were managed with resection surgery and 46 with a colonic stent. The colonic stent group had a higher Charlson index (9.5 ± 2.1 vs 8.6 ± 1.5, p = 0.01), a shorter time to oral intake (0.9 ± 1.1 vs 16.4 ± 53.5 days, p = 0.05), a shorter hospital stay (4 ± 4.8 vs 16.7 ± 15.5 days, p = 0.0001), less need for stomata (11.1 % vs 32.7 %, p = 0.01), fewer early complications (4.3 % vs 46.9 %, p = 0.0001) and more late complications (33.3 % vs 6.4 %, p = 0.001). Undergoing chemotherapy (p = 0.008) was the only independent factor related to increased survival. In the subgroup of patients managed with chemotherapy, surgical primary tumor resection was an independent factor associated with increased survival. CONCLUSION: both treatments are effective for resolving obstructive manifestations in patients diagnosed with stage-IV obstructive colorectal cancer. Resection surgery has no positive impact on survival and thus cannot be recommended as a therapy of choice.

Improved detection of colorectal adenomas by high-quality colon cleansing.

Background and study aims Reliable adenoma detection requires "adequate" bowel preparation. The adenoma detection rate (ADR) was assessed in patients with high-quality (stool-free) cleansing versus adequate cleansing. Patients and methods This study was a post-hoc combined analysis of three randomized trials individually powered for cleansing quality assessment. Treatment-independent ADR was assessed versus colon cleansing quality by central readers using the Harefield Cleansing Scale (HCS) and the Boston Bowel Preparation Scale (BBPS). The number needed to treat (NNT) to find an additional patient with at least one adenoma was calculated for high-quality versus adequate-quality cleansing. Results A total of 1749 patients were included. ADR increased with high-quality versus adequate-quality cleansing: HCS grade A versus B, 39 % (94/242) versus 27 % (336/1229); NNT = 8.7; P  < 0.001. ADR also increased with high-quality versus uniform adequate segmental cleansing scores: HCS grade A versus uniform segmental scores 2, 39 % (94/242) versus 26 % (97/379); NNT = 7.5; P  < 0.001. ADR increased with top-quality versus adequate segmental cleansing scores: HCS uniform segmental scores 4 versus 2, 54 % (21/39) versus 26 % (97/379); NNT = 3.6; P  < 0.001. ADR increased with BBPS 9 versus 6, 43 % (71/166) versus 26 % (247/950); NNT = 6.0; P  < 0.001. Right colon ADR increased with top-quality versus adequate cleansing: HCS 4 versus 2, 20 % (25/122) versus 11 % (121/1117); NNT = 10.4; P  < 0.001 and BBPS 3 versus 2, 15 % (42/284) versus 11 % (130/1192); NNT = 25.8; P  = 0.033. Conclusions High-quality colon cleansing improves adenoma detection, and it should be a priority for bowel preparations for colonoscopy.

Educational nurse-led telephone intervention shortly before colonoscopy as a salvage strategy after previous bowel preparation failure: a multicenter randomized trial.

BACKGROUND: The most important predictor of unsuccessful bowel preparation is previous failure. For those patients with previous failure, we hypothesized that a nurse-led educational intervention by telephone shortly before the colonoscopy appointment could improve cleansing efficacy. METHODS: We performed a multicenter, endoscopist-blinded, randomized controlled trial. Consecutive outpatients with previous inadequate bowel preparation were enrolled. Both groups received the same standard bowel preparation protocol. The intervention group also received reinforced education by telephone within 48 hours before the colonoscopy. The primary outcome was effective bowel preparation according to the Boston Bowel Preparation Scale. Intention-to-treat (ITT) analysis included all randomized patients. Per-protocol analysis included patients who could be contacted by telephone and the control cases. RESULTS: 657 participants were recruited by 11 Spanish hospitals. In the ITT analysis, there was no significant difference between the intervention and control groups in the rate of successful bowel preparation (77.3 % vs. 72 %; P = 0.12). In the intervention group, 267 patients (82.9 %) were contacted by telephone. Per-protocol analysis revealed significantly improved bowel preparation in the intervention group (83.5 % vs. 72.0 %; P = 0.001). CONCLUSION: Among all patients with previous inadequate bowel preparation, nurse-led telephone education did not result in a significant improvement in bowel cleansing. However, in the 83 % of patients who could be contacted, bowel preparation was substantially improved. Phone education may therefore be a useful tool for improving the quality of bowel preparation in those cases.

Narrow-band imaging and high-definition white-light endoscopy in patients with serrated lesions not fulfilling criteria for serrated polyposis syndrome: a randomized controlled trial with tandem colonoscopy.

BACKGROUND: It is unknown whether narrow-band imaging (NBI) could be more effective than high-definition white-light endoscopy (HD-WLE) in detecting serrated lesions in patients with prior serrated lesions > 5 mm not completely fulfilling serrated polyposis syndrome (SPS) criteria. METHODS: We conducted a randomized, cross-over trial in consecutive patients with prior detection of at least one serrated polyp ≥10 mm or ≥ 3 serrated polyps larger than 5 mm, both proximal to the sigmoid colon. Five experienced endoscopists performed same-day tandem colonoscopies, with the order being randomized 1:1 to NBI-HD-WLE or HD-WLE-NBI. All tandem colonoscopies were performed by the same endoscopist. RESULTS: We included 41 patients. Baseline characteristics were similar in the two cohorts: NBI-HD-WLE (n = 21) and HD-WLE-NBI (n = 20). No differences were observed in the serrated lesion detection rate of NBI versus HD-WLE: 47.4% versus 51.9% (OR 0.84, 95% CI: 0.37-1.91) for the first and second withdrawal, respectively. Equally, no differences were found in the polyp miss rate of NBI versus HD-WLE: 21.3% versus 26.1% (OR 0.77, 95% CI: 0.43-1.38). Follow-up colonoscopy in nine patients (22%) allowed them to be reclassified as having SPS. CONCLUSIONS: In patients with previous serrated lesions, the serrated lesion detection rate was similar with NBI and HD-WLE. A shorter surveillance colonoscopy interval increases the detection of missed serrated polyps and could change the diagnosis of SPS in approximately one in every five patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02406547, registered on April 2, 2015.

Variation in Colonoscopy Performance Measures According to Procedure Indication.

BACKGROUND & AIMS: Most fulfillment and benchmarking information for colonoscopy quality indicators has been obtained from studies of primary screening colonoscopies. We analyzed differences in the fulfillment of colonoscopy quality indicators based on the indication for endoscopy. METHODS: We performed an observational, multicenter, cross-sectional study of 14,867 patients who underwent endoscopy procedures for gastrointestinal symptoms (40.3%), a positive result from a fecal immunochemical test (36.0%), postpolypectomy surveillance (15.3%), or primary screening (8.4%), from February 2016 through December 2017 at 14 centers in Spain. We evaluated rates of adequate colon cleansing, cecal intubation, adenoma detection, and colorectal cancer detection, among others. We used findings from primary screening colonoscopies as the reference standard. RESULTS: Fewer than 90% of patients had adequate bowel preparation; 83.1% of patients with gastrointestinal symptoms had adequate bowel preparation (odds ratio [OR] compared with patients with primary screening colonoscopies, 0.62; 95% CI, 0.49-0.78) and 85.3% of patients receiving postpolypectomy surveillance had adequate bowel preparation (OR, 0.71; 95% CI, 0.55-0.91). The cecal intubation rate was also lower in patients with gastrointestinal symptoms (93.1%) (OR, 0.34; 95% CI, 0.22-0.52). The adenoma detection rate was higher in patients with a positive result from a fecal immunochemical test (46.4%) (OR, 2.01; 95% CI, 1.71-2.35) and in patients undergoing postpolypectomy surveillance (48.2%) (OR, 1.41; 95% CI, 1.20-1.67). The highest proportion of patients with colorectal cancer was in the gastrointestinal symptom group (5.1%) (OR, 5.24; 95% CI, 2.30-11.93) and the lowest was in patients undergoing surveillance (0.8%) (OR, 0.83; 95% CI, 0.32-2.14). CONCLUSIONS: Fulfillment of colonoscopy performance measures varies substantially by indication. Policies addressing performance measures beyond colonoscopy screening procedures should be developed. Benchmarking recommendations could be adjusted according to colonoscopy indication.

Narrow band imaging and white light endoscopy in the characterization of a polypectomy scar: A single-blind observational study.

AIM: To assess the incremental benefit of narrow band imaging (NBI) and white light endoscopy (WLE), randomizing the initial technique for the detection of residual neoplasia at the polypectomy scar after an endoscopic piecemeal mucosal resection (EPMR). METHODS: We conducted an observational study in an academic center to assess the incremental benefit of NBI and WLE randomly applied 1:1 (NBI-WLE or WLE-NBI) in the follow-up of a post-EPMR scar by the same endoscopist. RESULTS: A total of 112 EPMR scars were included. The median baseline polyp size was 20 mm (interquartile range: 14-30). At first review, NBI and WLE showed good sensitivity (85.0% vs 78.9%), specificity (77.1% vs 84.2%) and overall accuracy (80.0% vs 82.5%). NBI after WLE (WLE-NBI group) improved accuracy, but this difference was not statistically significant [area under the curve (AUC): 86.8% vs 81.6%, P = 0.15]. WLE after NBI (NBI-WLE group) did not improve accuracy (AUC: 81.4% vs 81.1%, P = 0.9). Overall, recurrence was found in 39/112 (34.8%) lesions. CONCLUSION: Although no statistically significant differences were found between the two techniques at the first post-EPMR assessment, the use of NBI after WLE may improve residual neoplasia detection. Nevertheless, biopsy is still required in the first scar review.

Routine lower gastrointestinal endoscopy for radiographically confirmed acute diverticulitis. In whom and when is it indicated?

INTRODUCTION: international guidelines recommend a routine colonoscopy to rule out advanced neoplasm after an acute diverticulitis event. However, in recent years, this recommendation has been called into question following the advent of computerized tomography (CT), particularly with regard to uncomplicated diverticulitis. Furthermore, colonoscopy is associated with a risk and additional costs. OBJECTIVE: to understand the diagnostic yield, quality and safety of colonoscopy in the setting of acute diverticulitis. METHODS: this was a retrospective study of all patients diagnosed with acute diverticulitis via CT between 2005 and 2013, who subsequently underwent a colonoscopy. RESULTS: two hundred and sixteen patients diagnosed with acute diverticulitis via CT were enrolled. These included 58 cases with complicated diverticulitis (27%) and 158 with uncomplicated diverticulitis (73%). An advanced neoplasm was found in 12 patients (5.6%); 11.7% were complicated and 3.2% were uncomplicated (p = 0.02). No major complications were identified. The quality was low but improved over time; the complete procedure rate was 88%, an effective preparation was achieved in 75% and excision of polyps < 2 cm was performed in 78% of cases. The optimum colonoscopy quality cu-off was 9.5 weeks. CONCLUSION: routine colonoscopy is advisable after a complicated diverticulitis event but its recommendation is unclear with regard to uncomplicated episodes. Colonoscopy is safe even when performed early. The overall quality is low but may be optimized via a subsequent endoscopy, two months after a diverticulitis diagnosis.

Efficacy of a multifactorial strategy for bowel preparation in diabetic patients undergoing colonoscopy: a randomized trial.

Background and study aims: Previous studies have reported that diabetes mellitus is an independent risk factor for inadequate bowel preparation. Current guidelines do not recommend a specific preparation for this patient population. The aims of this study were to assess the efficacy, safety, and tolerability of an adapted preparation protocol for colon cleansing in patients with type 2 diabetes mellitus. Patients and methods: This randomized, single-blind, parallel group, superiority trial compared a conventional bowel preparation protocol (CBP) with a diabetes-specific preparation protocol (DSP). The CBP included a low-fiber diet for 3 days followed by a clear liquid diet for 24 hours before colonoscopy. The DSP included a multifactorial strategy combining an educational intervention, a low-fiber diet, and adjustment of blood glucose-lowering agents. All patients received 4 L of a polyethylene glycol solution in a split-dose regimen. The endoscopists were blinded to the preparation protocol. The primary outcome measure was inadequate bowel preparation according to the Boston Bowel Preparation Scale. Secondary outcome measures included hypoglycemic events, tolerability, and acceptability. Results: A total of 150 patients were included in the study (74 CBP and 76 DSP). Both groups were comparable in terms of baseline characteristics. Inadequate bowel cleansing was more frequent following CBP than DSP (20 % vs. 7 %, P = 0.014; risk ratio 3.1, 95 % confidence interval 1.2 - 8). Only CBP and performance status were independently associated with inadequate bowel preparation. Both preparations were equally tolerated and accepted by patients, and side-effects were similar between the groups. Conclusions: A multifactorial strategy for bowel preparation in patients with diabetes undergoing colonoscopy showed a threefold reduction in the rate of inadequate bowel preparation, with no differences in safety and tolerability compared with conventional preparation. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02300779).