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1 Early biliary decompression versus conservative treatment in 2 acute biliary pancreatitis (APEC trial): design and rationale of a 3 randomised multicenter trial [ISRCTN97372133] 4 5 Nicolien J Schepers1,2, Olaf J Bakker3, Marc GH Besselink4, Thomas L Bollen5, Marcel GW 6 Dijkgraaf6, Casper HJ van Eijck7, Paul Fockens8, Erwin JM van Geenen9, Janneke van 7 Grinsven4,8, Nora DL Hallensleben1,10, Bettina E Hansen1, Hjalmar C van Santvoort10, Robin 8 Timmer1, Marie-Paule GF Anten11, Clemens JM Bolwerk12, Foke van Delft13, Hendrik M van 9 Dullemen14, G Willemien Erkelens15, Jeanin van Hooft8, Robert Laheij16, René WM van der 10 Hulst17, Jeroen M Jansen18, Frank JGM Kubben19, Sjoerd D Kuiken20, Lars E Perk21, Rogier 11 JJ de Ridder22, Marno CM Rijk23, Tessa EH Römkens24, Erik J Schoon25, Matthijs P 12 Schwartz26, BW Marcel Spanier27, Adriaan CITL Tan28, Willem J Thijs29, Niels G Venneman30, 13 Frank P Vleggaar31, Wim van de Vrie32, Ben J Witteman33, Hein G Gooszen34 and Marco J 14 Bruno1 15 for the Dutch Pancreatitis Study Group 16 17 Corresponding author 18 Nicolien J Schepers, MD 19 Dutch Pancreatitis Study Group 20 St. Antonius Hospital 21 Koekoekslaan 1 22 3430 EM Nieuwegein 23 The Netherlands 24 Tel: +31 614411960 25 Fax: +31 306098316 26 E-mail: [email protected] 27 1 28 Author details 29 1. Dept. of Gastroenterology and Hepatology, Erasmus Medical Center, PO 2040, 3000 CA 30 Rotterdam; the Netherlands 31 2. Dept. of Gastroenterology and Hepatology, St Antonius Hospital, PO 2500, 3430 EM 32 Nieuwegein; the Netherlands 33 3. Dept. of Surgery, University Medical Center Utrecht, PO 85500, 3508 GA Utrecht; the 34 Netherlands 35 4. Dept. of Surgery, Academic Medical Center University of Amsterdam, PO 22660, 1100 DD 36 Amsterdam; the Netherlands 37 5. Dept. of Radiology, St Antonius Hospital, PO 2500, 3430 EM Nieuwegein; The 38 Netherlands 39 6. Clinical Research Unit, Academic Medical Center University of Amsterdam, PO 22660, 40 1100 DD Amsterdam; the Netherlands 41 7. Dept. of Surgery, Erasmus Medical Center, PO 2040, 3000 CA Rotterdam; the 42 Netherlands 43 8. Dept. of Gastroenterology and Hepatology, Academic Medical Center University of 44 Amsterdam, PO 22660, 1100 DD Amsterdam; the Netherlands 45 9. Dept. of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, 46 HP 690, PO 9101, 6500 HB Nijmegen; the Netherlands 47 10. Dept. of Surgery, St Antonius Hospital, PO 2500, 3430 EM Nieuwegein; the Netherlands 48 11. Dept. of Gastroenterology and Hepatology, Sint Franciscus Gasthuis, PO 10900, 3004 49 BA, Rotterdam; the Netherlands 50 12. Dept. of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Reinier de 51 Graafweg 3-11, 2625 AD Delft; the Netherlands 52 13. Dept. of Gastroenterology and Hepatology, VU University Medical Center Amsterdam, 53 PO Box 7057, 1007 MB Amsterdam; the Netherlands 54 14. Dept. of Gastroenterology and Hepatology, University Medical Center Groningen, PO 55 30001, 9700 RB Groningen; the Netherlands 2 56 15. Dept. of Gastroenterology and Hepatology, Gelre Hospital, PO 9014, 7300 DS 57 Apeldoorn; the Netherlands 58 16. Dept. of Gastroenterology and Hepatology, St. Elisabeth Hospital, PO 90151, 5000 LC 59 Tilburg; the Netherlands 60 17. Dept. of Gastroenterology and Hepatology, Kennemer Gasthuis, PO 417, 2000 AK 61 Haarlem; the Netherlands 62 18. Dept. of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis; Postbus 63 95500, 1090 HM Amsterdam; the Netherlands 64 19. Dept. of Gastroenterology and Hepatology, Maasstad Hospital, Maasstadweg 21, 3079 65 DZ Rotterdam; the Netherlands 66 20. Dept. of Gastroenterology and Hepatology, Sint Lucas Andreas Hospital, PO 9243 67 1006 AE Amsterdam; the Netherlands 68 21. Dept. of Gastroenterology and Hepatology, Medical Center Haaglanden, PO 432 69 2501 CK Den Haag; the Netherlands 70 22. Dept. of Gastroenterology and Hepatology, Maastricht University Medical Center, PO 71 5800, 6202 AZ Maastricht; the Netherlands 72 23. Dept. of Gastroenterology and Hepatology, Amphia Hospital, PO 90158, 4800 RK Breda; 73 the Netherlands 74 24. Dept. of Gastroenterology and Hepatology, Jeroen Bosch Hospital, PO 90153, 5200 ME 75 ‘s-Hertogenbosch; the Netherlands 76 25. Dept. of Gastroenterology and Hepatology, Catharina Hospital, PO 1350, 5602 ZA 77 Eindhoven; the Netherlands 78 26. Dept. of Gastroenterology and Hepatology, Meander Medical Center, PO 1502, 3800 79 BM, Amersfoort; the Netherlands. 80 27. Dept. of Gastroenterology and Hepatology, Rijnstate Hospital, PO 9555, 6800 TA 81 Arnhem; the Netherlands 82 28. Dept. of Gastroenterology and Hepatology, Canisius-Wilhelmina Hospital, PO 9015, 6500 83 GS Nijmegen; the Netherlands. 3 84 29. 85 9700 RM Groningen; the Netherlands 86 30. Dept. of Gastroenterology and Hepatology, Medisch Spectrum Twente, PO 50000, 7500 87 KA Enschede; the Netherlands. 88 31. Dept. of Gastroenterology and Hepatology, University Medical Center Utrecht, PO 85500, 89 3508 GA Utrecht; the Netherlands 90 32. Dept. of Gastroenterology and Hepatology, Albert Schweitzer Hospital, PO 444 91 3300 AK Dordrecht; the Netherlands 92 33. Dept. of Gastroenterology and Hepatology, Hospital Gelderse Vallei Ede, PO 9025, 6710 93 HN Ede; the Netherlands 94 34. Dept. of Operating Rooms - Evidence Based Surgery, Radboud University Nijmegen 95 Medical Centre, HP 690, PO 9101, 6500 HB Nijmegen; the Netherlands. Dept. of Gastroenterology and Hepatology, Martini Hospital, PO 30033 96 4 97 Abstract (max 350 words, now 262) 98 99 Background: Acute pancreatitis is mostly caused by gallstones or sludge. Early 100 decompression of the biliary tree by endoscopic retrograde cholangiography (ERC) with 101 sphincterotomy may improve outcome in these patients. Whereas current guidelines 102 recommend early ERC in patients with concomitant cholangitis, early ERC is not 103 recommended in patients with mild biliary pancreatitis. Evidence on the role of routine early 104 ERC with endoscopic sphincterotomy in patients without cholangitis but with biliary 105 pancreatitis at high risk for complications is lacking. We hypothesize that early ERC with 106 sphincterotomy improves outcome in these patients. 107 Methods/Design: The APEC trial is a randomised controlled, parallel-group, superiority 108 multicenter trial. Within 24 hours after presentation to the emergency department, patients 109 with biliary pancreatitis without cholangitis and at high risk for complications, based on Acute 110 Physiology And Chronic Health Evaluation (APACHE-II) score of 8 or more, Modified 111 Glasgow score of 3 or more, or serum C-reactive protein above 150 mg/L, will be 112 randomised. In 27 hospitals of the Dutch Pancreatitis Study Group, 232 patients will be 113 allocated to early ERC with sphincterotomy or to conservative treatment. The primary end 114 point is a composite of major complications (i.e. organ failure, pancreatic necrosis, 115 pneumonia, bacteremia, cholangitis, pancreatic endocrine or exocrine insufficiency) or death 116 within 180 days after randomization. Secondary end points include ERC related 117 complications, infected necrotising pancreatitis, length of hospital stay and an economical 118 evaluation. 119 Discussion: The APEC trial investigates whether an early ERC with sphincterotomy reduces 120 the composite end point of major complications or death compared with conservative 121 treatment in patients with biliary pancreatitis at high risk of complications. 122 Trial registration: Current Controlled Trials ISRCTN97372133 123 124 Keywords (max 10): Acute pancreatitis, Treatment, Endoscopy, Pancreas, ERCP, ERC 5 125 Background 126 127 Acute pancreatitis is a leading cause for acute hospitalization [1]. In most cases pancreatitis 128 results from gallstones causing obstruction of Vater’s ampulla [2, 3]. As biliary stones or 129 sludge are thought to initiate and aggravate pancreatitis, early biliary decompression – 130 achieved by endoscopic retrograde cholangiography (ERC) with sphincterotomy – may 131 ameliorate the disease course [4, 5]. In return, ERC with sphincterotomy itself may also be 132 associated with complications in up to 10% of patients [6, 7]. 133 Several studies have investigated the effect of routine ERC in biliary pancreatitis [8]. 134 Guidelines state an undisputed indication for ERC in patients with concurrent cholangitis and 135 pancreatitis [2, 9]. In patients with mild disease, early ERC is not indicated because in these 136 patients the risk for complications does not outweigh the potential benefit [2, 9]. 137 Recent guidelines advise to perform ERC with sphincterotomy in case of pancreatitis 138 with cholestasis, but acknowledge the moderate quality of evidence for this recommendation 139 [2, 9]. In patients with pancreatitis at high risk for developing complications (i.e. predicted 140 severe) without cholangitis, data are conflicting. A meta-analysis found no beneficial effect of 141 routine early ERC compared with conservative treatment [8]. However, the studies have 142 notable shortcomings that preclude reliable recommendations on the use of ERC in patients 143 with predicted severe biliary pancreatitis without cholangitis [10]. First, patients included were 144 those with a low pre-likelihood of a biliary etiology, those at low risk for developing 145 complications (i.e. predicted mild), and those with cholangitis at presentation. Second, 146 patient selection criteria and study end points (complications) varied considerably between 147 studies and also included clinically less relevant complications such as pleural effusion or 148 ascites. Third, the trials did not present data separately regarding liver biochemical tests, 149 which precludes performing a subgroup analysis for patients with cholestasis. Fourth, routine 150 ‘early’ ERC was performed during a wide time frame (48 to 72 hours after admission) which 151 may be too late to prevent complications from severe disease or increase the risk for ERC 152 related complications. Fifth, the trial protocols did not specify precisely when sphincterotomy 6 153 should be performed. This resulted in many patients who underwent ERC without 154 sphincterotomy. We believe sphincterotomy should routinely be performed during ERC to 155 decompress the biliary duct, even in the absence of gallstones or visible sludge in the 156 common bile duct [11-13]. Sixth, no criteria were set to guarantee that ERCs were performed 157 by experienced endoscopists, although ERC is an intervention that requires considerable 158 training and expertise [14, 15]. Finally, even if the data of all available randomised trials are 159 pooled, such analysis will still not have sufficient power to detect clinically relevant and 160 statistically significant effects of early ERC with sphincterotomy on major complications or 161 death in patients with predicted severe biliary pancreatitis without cholangitis [16, 8]. 162 The APEC trial is designed to investigate whether early ERC with sphincterotomy 163 compared with conservative treatment improves outcome in patients with biliary pancreatitis 164 without cholangitis who are at high risk for complications. 165 7 166 Methods/Design 167 168 The APEC trial is a randomised controlled, parallel-group, superiority, multicenter trial. 169 Patients with acute pancreatitis will be assessed for study eligibility within 24 hours after 170 presentation to the emergency department. Patients with biliary pancreatitis without 171 cholangitis and at high risk of developing severe disease are eligible for randomisation. 172 Patients are randomised to early ERC with sphincterotomy or to conservative treatment. The 173 trial will be conducted in 27 hospitals of the Dutch Pancreatitis Study Group. The APEC trial 174 protocol is in accordance with the Spirit Guidelines [17]. 175 176 Primary end point (see Table 1 for definitions) 177 The primary end point is a composite of major complications or death occurring within 180 178 days after randomisation (i.e. the composite end point can only occur once per patient). 179 Major complications are defined as persistent organ failure, pancreatic necrosis, bacteremia, 180 cholangitis, pneumonia and pancreatic endocrine or exocrine insufficiency. 181 182 Secondary end points 183 “Per protocol” analysis of the primary endpoint 184 “As treated” analysis of the primary endpoint 185 Individual components of the primary end point 186 Infected necrotising pancreatitis 187 Need for new intensive care unit admission 188 Length of stay at intensive care unit 189 ERC related complications (see Table 2 for definitions) 190 Cholangitis during admission 191 Number of endoscopic, radiological and operative (re-)interventions 8 192 Readmission for biliary events (recurrent acute biliary pancreatitis, cholecystitis, biliary 193 colics, cholangitis) 194 Difficulty of cholecystectomy (as scored by Visual Analogue Scale 1-10) 195 Quality of life (Short Form-36 and EQ5D-5L) including quality adjusted life year’s (QALY) 196 Direct medical costs, direct and indirect non-medical costs 197 198 Inclusion criteria 199 Acute pancreatitis; defined as the presence of at least 2 out of the following 3 criteria: 1) 200 pain in the upper abdomen, 2) serum amylase or lipase concentration > 3 times the 201 upper limit of normal or 3) imaging features of acute pancreatitis on Computed 202 Tomography (CT) or Magnetic Resonance Imaging (MRI) [18] 203 High risk of developing severe disease (i.e. predicted severe) based on either one of the 204 following criteria: Acute Physiology and Chronic Health Evaluation (APACHE II score) ≥ 8 205 [19] (see Table 4) 2) Modified Glasgow score ≥ 3 [20] (see Table 3), or 3) C-reactive 206 protein >150 mg/L [21, 22]. 207 High probability of a biliary aetiology based on at least one of the following criteria: 1) 208 gallstones or biliary sludge on imaging (any type), 2) dilated common bile duct on 209 imaging defined as >8mm in patients ≤75 years or >10mm in patients >75 years, 3) 210 alanine aminotransferase (ALAT) > two times upper limit of normal (no absolute 211 numerical value is chosen because of multicentric design with varying upper limits 212 between hospitals and gender-based differences in upper limit of normal values [23-25]) 213 214 215 Ability to perform ERC within 24 hours after presentation to the emergency department and no more than 72 hours after symptom onset 216 In case of a previous episode of necrotising pancreatitis, patient should be fully recovered (confirmed on imaging) 217 Age ≥18 years 218 Written informed consent 9 219 220 Exclusion criteria 221 Cholangitis (see Table 1 for definition) 222 Pancreatitis due to other causes such as alcohol abuse (more than 4 units per day), 223 metabolic causes (hypertriglyceridemia, hypercalcemia), medication, trauma, etc. 224 Previous pancreatic sphincterotomy or needle knife precut 225 Chronic pancreatitis (see Table 5 for definition) 226 International Normalized Ratio that cannot be corrected to less than 1.5 with clotting 227 228 factors or fresh frozen plasma Pregnancy 229 230 Randomisation 231 Patients are randomised to early ERC with sphincterotomy or to conservative treatment (1:1 232 ratio) with a web-based randomization module (ALEA, Academic Medical Center, 233 Amsterdam) in random blocks of size two, four or six. At randomisation, patients are stratified 234 according to the presence of cholestasis and for region of the hospital. Cholestasis is defined 235 as a serum bilirubin >40 μmol/L at randomization or a dilated common bile duct (defined as 236 >8mm in patients ≤75 years or >10mm in patients >75 years). 237 238 Treatment protocol 239 240 Early ERC with sphincterotomy is performed within 72 hours after symptom onset and within 241 24 hours of hospital admission. A sphincterotomy is always performed irrespective of the 242 presence of common bile duct stones. ERC is performed by or under the direct supervision 243 of an experienced endoscopist defined as a person who has done more than 400 ERCs in 244 his or her lifetime and has performed more than 50 ERCs yearly on average in the previous 245 three years. When unable to cannulate the common bile duct, even after precut Early ERC with sphincterotomy 10 246 sphincterotomy, the ERC procedure will be ended and the patient is treated conservatively. 247 After the patient has recovered from the acute pancreatitis attack, a repeat ERC is scheduled 248 to perform a full sphincterotomy. According to the intention-to-treat principle, these patients 249 will be analyzed according to their original treatment allocation: i.e. early ERC with 250 sphincterotomy. In case of incomplete stone-extraction a plastic endoprosthesis is inserted 251 and an elective ERC is scheduled. Antibiotics are only administered in case of contrast 252 injection without adequate biliary drainage. 253 254 255 Patients in the conservative group are managed according to the conservative supportive 256 treatment regimen for patients with acute biliary pancreatitis as described in the paragraph 257 below. A rescue ERC is performed when a patient develops cholangitis (see Table 1 for 258 definition). Whenever the attending physician is in doubt whether or not an ERC should be 259 performed, the study coordinator presents the case to an expert panel. This expert panel, 260 consisting of an independent gastroenterologist and a gastrointestinal surgeon, provides a 261 treatment advice within 24 hours. Retained bile duct stones are removed during an elective 262 ERC when the patient is recovered from the initial pancreatitis episode. Conservative treatment 263 264 General treatment regimen 265 Both groups are treated with intravenous infusion of fluids to ensure adequate hydration and 266 diuresis, appropriate analgesic treatment, enteral nutrition if necessary, treatment of 267 endocrine and exocrine pancreatic insufficiency, and a gastric tube in case of vomiting. No 268 antibiotic prophylaxis is given. The treating physician assesses whether the patient requires 269 intensive care monitoring or further supportive measures (e.g. mechanical ventilation). All 270 patients will undergo a contrast-enhanced CT (CECT) 5 to 7 days after hospital admission for 271 assessment of pancreatic necrosis. In case patients quickly recover and are discharged 272 within 5 days, CECT will not be routinely performed and the disease will be considered mild. 273 Readmission within 10 days after initial discharge for complications related to pancreatitis is 11 274 regarded as primary admission. The timing of cholecystectomy is determined by the treating 275 physician depending on the patient’s condition and outcome of pancreatitis. 276 277 Data collection 278 Clinical data are collected using case record forms. At all sites an independent monitor will 279 assess the study forms including informed consent documents and compare these with 280 source-documents. The in-hospital utilization of healthcare will be registered as part of the 281 data collection. Out-of-hospital use of healthcare will be documented by self-administered 282 questionnaires. 283 284 Follow-up 285 After hospital discharge patients are seen at the outpatients clinic and further monitored at 286 the discretion of the physician. After 1, 3, and 6 months patients receive a questionnaire (SF- 287 36, SF-HLQ and EQ5D-5L) [26, 27]. A visit is scheduled at 3 months after randomization to 288 identify persistent common bile duct stones or detect endocrine or exocrine pancreatic 289 insufficiency (serum liver- and glucose measurements and fecal elastase). 290 291 Safety 292 An independent Data Safety Monitoring Committee (DSMC) is appointed to assess protocol 293 adherence, patient recruitment, and patient safety. All physicians who are involved in the trial 294 are asked to report all adverse events to the coordinating investigator. Adverse events are 295 reported using the online module (https://www.toetsingonline.nl) of the Dutch Central 296 Committee on Research involving human subjects. All adverse events are collected and 297 reported unblinded to the DSMC every time 60 patients are randomised, after randomization 298 of the final patient, and at the end of follow-up of the final patient. In addition, a continuous 299 sequential safety analysis on mortality is performed to ensure patient’s safety throughout the 300 trial. The DSMC discusses all adverse events and the progress of the trial, and reports to the 12 301 trial steering committee. A copy is sent to the ethical committee and all physicians who are 302 involved with the study. 303 304 Ethics 305 The APEC trial is performed in accordance to the declaration of Helsinki and the Dutch law 306 regarding research involving human subjects (Wet Medisch wetenschappelijk Onderzoek 307 met Mensen). The ethical committee of the Erasmus Medical Center in Rotterdam, the 308 Netherlands, approved the study protocol on the 12th of December 2012. Subsequently, the 309 boards of the 27 participating hospitals gave permission for conducting the trial. The APEC 310 trial is registered with identification number ISRCTN97372133. 311 312 Statistical considerations 313 314 The sample size calculation is based on a recent Dutch multicenter, observational study in 315 patients with biliary pancreatitis at high risk for complications [11]. The primary end point 316 occurred in 32% of patients in which ERC was performed compared with 46% of patients 317 who were treated conservatively. Taken into account that ERC was not always performed 318 within 24 hours and that sphincterotomy was not routinely performed, a correction factor of 319 2% for both percentages is added to both incidence rates. The APEC trial is a superiority trial 320 in which the sample size calculation is based on the assumption that early ERC with 321 sphincterotomy reduces the incidence of the primary end point by 18% (48% to 30%). With a 322 power of 80%, a two sided significance level of 5% and a 1% drop-out rate, a total of 232 323 patients are required to be included in the study. Sample size calculation 324 325 326 The following patient characteristics before randomization will be described: age, sex, body 327 mass index, co-morbidity, American Society of Anaesthesiologists (ASA) score, duration of 328 symptoms before randomization, duration of symptoms before ERC, serum bilirubin levels, Descriptive statistics 13 329 dilated common bile duct on ultrasound or computed tomography, presence of (multi) organ 330 failure or systemic inflammatory response syndrome (SIRS), Sequential Organ Failure 331 Assessment (SOFA) scale [28], Multiple Organ Dysfunction Score (MODS) [29], predicted 332 disease severity according to APACHE-II, modified Glasgow, blood urea nitrogen and C- 333 reactive protein. Data will be presented in percentages for categorical variables. Continuous 334 data with normal distribution will be presented as mean with standard deviation, and as 335 median with interquartile range in case of skewed distribution. 336 337 338 After 232 patients in total have completed their 6 months follow-up, raw data regarding 339 potential end points will be presented to an adjudication committee blinded for treatment 340 allocation to determine whether end points meet the protocol-specified criteria. In case of 341 dissenting opinions, a consensus meeting will follow. Primary analysis, using the Pearson’s 342 Chi-squared test, is based on the intention-to-treat principle with patients being analyzed 343 according to original treatment allocation, irrespective whether cannulation or sphincterotomy 344 was successful. For exploratory reasons a per-protocol analysis will be performed to 345 compare treatment groups. A tabular listing of all patients excluded from the intention-to-treat 346 populations will be provided together with the reasons for exclusion. Data will be presented 347 as relative risks with 95% confidence intervals. A two-tailed P<0.05 is considered statistically 348 significant. Analyses 349 350 351 Predefined subgroup analysis will be done according to the presence of cholestasis. Logistic 352 regression models will be used to test whether treatment effects differ significantly between 353 these subgroups. Secondary end points will be compared using the Pearson’s chi-squared 354 test or Mann-Whitney U test. Additionally, secondary end points will be analyzed separately 355 using Cox regression analysis censoring patients no longer at risk and categorising missing 356 data as no event. For all other analyses, data will be considered missing at random. To Additional analyses 14 357 evaluate differences in systemic inflammatory response after randomisation, the APACHE-II, 358 C-reactive protein levels and presence of SIRS from randomization to day 7 will be 359 calculated and compared between treatment groups. To gain further insight into factors that 360 are predictive of major complications or death after ERC, exploratory analysis of the effects 361 of (essential) baseline covariates (and potential interactions) will be performed using logistic 362 regression analysis. 363 Direct medical and non-medical costs, and indirect costs will be compared to assess 364 costs per patient with poor outcome (death or severe complications). Validated 365 questionnaires will be analyzed to assess differences in quality of life and provide input to 366 compare costs per quality adjusted life year (QALY). Health utility scoring algorithms for the 367 EQ5D-5L health status profiles available from the literature, based on preferences in the 368 general population using time trade-off elicitation techniques, will be used to derive a QALY 369 estimate for each patient. This QALY will be calculated as the product sum of health utilities 370 and the lengths of the periods in-between successive measurements [30, 31]. 371 372 373 An interim-analysis will be performed when 116 patients (50%) are randomised and 374 discharged after their initial hospital admission. Raw data pertaining to potential end points 375 will be presented to an adjudication committee blinded for treatment allocation to determine 376 whether end points meet the protocol-specified criteria. In case of dissenting opinions, a 377 consensus meeting will follow. The interim-analysis will be performed by an independent 378 statistician who reports to the DSMC. The DSMC will have unblinded access to all data when 379 discussing the results of the interim-analysis and reports to the steering committee. The 380 steering committee will decide upon continuation of the APEC trial. The Haybittle-Peto 381 approach is used for beneficial effect, meaning that the trial will be ended using symmetric 382 stopping boundaries at P<0.001 [32, 33]. The trial will not be stopped for futility. Premature termination of the study 15 383 Discussion 384 385 The APEC trial is designed to provide an answer to a persisting clinical dilemma; whether or 386 not to routinely perform early ERC with sphincterotomy in patients with biliary pancreatitis at 387 high risk for complications, but without concurrent cholangitis. Guidelines clearly advise 388 urgent ERC with sphincterotomy in patients with concomitant cholangitis and discard this 389 intervention in patients with a predicted mild disease course. A recent Cochrane meta- 390 analysis comparing routine ERC versus conservative treatment found no difference in 391 complications and death in patients with pancreatitis at high risk for complications [8]. 392 However, besides some notable limitations in the design of the studies included, the pooled 393 sample size of patients with biliary pancreatitis who were at high risk for complications 394 without concurrent cholangitis was too small to detect a difference in effect. As long as the 395 precise role of early ERC in biliary pancreatitis in patients at high risk for complications 396 without concurrent cholangitis remains unclear, patients are either withheld a potentially 397 beneficial intervention or exposed to a treatment from which they cannot benefit and may 398 only suffer its potential complications. The APEC trial is the first randomised controlled trial in 399 this particular subset of patients that is adequately powered to detect statistically significant 400 differences in clinically relevant outcomes of early ERC and sphincterotomy. The APEC trial 401 will also provide insights into the cost-effectiveness of routine early ERC and sphincterotomy 402 and the amount of cost savings that can be achieved. 403 404 To date, the optimal timing of early ERC in biliary pancreatitis is unclear. Previous studies 405 suggest that the severity of the pancreatitis is related to the duration of biliopancreatic ductal 406 obstruction [34, 35]. These observations provide the rationale to perform an ERC and 407 sphincterotomy early after the onset of symptoms. For this reason, albeit logistically 408 challenging, in the APEC trial ERC with sphincterotomy is performed within 72 hours after 409 symptom onset and within 24 hours after hospital admission to achieve the optimal effect of 410 the intervention. 16 411 Recent guidelines state that early ERC is probably beneficial in patients with cholestasis 412 [2], albeit with the acknowledgement that the level of evidence is low to moderate. To 413 investigate whether the potential beneficial effects of ERC with sphincterotomy depend on 414 the presence of cholestasis, patients in the APEC trial will be stratified according to this 415 baseline variable. 416 The primary end point of the APEC trial is a composite of major complications and death. 417 One of the major complications that may occur in the course of biliary pancreatitis is 418 pancreatic necrosis. Opposed to the definition of necrotising pancreatitis according to the 419 recently updated Atlanta classification, we excluded extrapancreatic necrosis alone as a 420 major complication [18] the rationale being that extrapancreatic necrosis alone is suggested 421 to be a separate entity in necrotising pancreatitis associated with less complications 422 compared with pancreatic necrosis [36]. 423 Commonly used biochemical and radiologic predictors of biliary obstruction are unreliable 424 in the early phase of acute pancreatitis [37]. Advanced imaging modalities such as magnetic 425 resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) have 426 improved accuracy in detecting common bile duct stones and could therefore be applied to 427 select patients for therapeutic ERC [38]. However, EUS is not available in all centres. 428 Moreover, performing either MRCP or EUS within 24 hours after presentation can be 429 challenging and proof to be unfeasible because of limited local resources and expertise, 430 particularly during on call hours. The use of MRCP and EUS before ERC is also not 431 incorporated in the APEC-trial because it is hypothesised that the beneficial effect of an early 432 sphincterotomy might also be present irrespective of a stone or visible sludge in the CBD 433 [11]. Hence, even if CBD stones are detected by EUS or MRCP, the question remains 434 whether sphincterotomy in the early phase of the disease improves outcome in these 435 patients. 436 The APEC trial will be performed in 27 centers that participate in the Dutch Pancreatitis 437 Study Group. The fact that ERCs will not be performed exclusively in high volume expert 438 centers, but in hospitals nationwide by endoscopists with a predefined skill level ensures that 17 439 the results of the APEC trial can be extrapolated to comparable clinical practice settings 440 worldwide. 441 442 Conclusion 443 The APEC trial is a multicenter randomised trial that investigates whether routine early ERC 444 with sphincterotomy reduces the composite end point of major complications or death in 445 patients with biliary pancreatitis at high risk for complications, but without cholangitis, as 446 compared with conservative treatment. 447 448 449 Trial Status 450 The trial was registered on the 7th of December 2012 in the ISRCTN register. The first 451 patient was randomised on the 1st of March 2013. To date, 144 patients have been 452 randomised and inclusion is on schedule. 453 454 455 Abbreviations 456 ALAT: alanine aminotransferase; 457 APACHE: Acute Physiology and Chronic Health Evaluation; 458 CBD: Common Bile Duct; 459 CECT: Contrast-Enhanced Computed Tomography; 460 CT: Computed Tomography; 461 DSMC: Data Safety Monitoring Committee; 462 EUS: Endoscopic UltraSound; 463 ISRCTN: International Standard Randomised Controlled Trial Number; 464 MRCP: Magnetic Resonance Cholangio Pancreatography; 465 MRI: Magnetic Resonance Imaging 466 QALY: Quality Adjusted Life Year. 18 467 468 Competing interests 469 The authors declare that they have no competing interests. 470 471 Authors’ contributions 472 NJS drafted the manuscript. OJB, MGHB, HvS, MJB co-authored the writing of the 473 manuscript. NJS, OJB, MGHB, HCvS, EJvG, BEH, RT, PF, HGG, MGWD and MJB 474 participated in the design of the study during several meetings of the Dutch Pancreatitis 475 Study Group. NJS and MGWD performed the sample size calculation. 476 All authors critically assessed the study design, edited the manuscript and read and 477 approved the final manuscript. 478 479 Acknowledgements 480 Funding 481 Fonds NutsOhra (grant number 1203-052), The Netherlands Organization for Health 482 Research and Development, Health Care Efficiency Research program (ZonMw, grant 483 number 837002008) and the patient organization for pancreatic diseases financially 484 supported the APEC trial. The APEC trial is an investigator initiated trial. The sponsors had 485 no influence on the design of the study, data collection, results or publications. 486 487 Steering committee 488 M.J. Bruno, MD PhD, department of Gastroenterology and Hepatology, Erasmus MC 489 University Medical Center (chair) 490 B.E. Hansen, MD PhD, department of Gastroenterology and Hepatology, Erasmus MC 491 University Medical Center, Rotterdam 492 C.H.J. van Eijck, MD PhD, department of Surgery, Erasmus MC University Medical Center, 493 Rotterdam 494 E.J. van Geenen, MD PhD, department of Gastroenterology and Hepatology, Radboud 19 495 University Medical Center, Nijmegen 496 T.L. Bollen, MD, department of Radiology, St. Antonius Hospital Nieuwegein 497 M.G.H. Besselink, MD PhD, department of Surgery, AMC Amsterdam 498 O.J. Bakker, MD, department of Surgery, UMC Utrecht 499 H.C. van Santvoort, MD PhD, department of Surgery, UMC Utrecht 500 P. Fockens, MD PhD, department of Gastroenterology and Hepatology, AMC Amsterdam 501 H.G. Gooszen, MD PhD, department of Operation Rooms/Evidence Based Surgery, UMC St 502 Radboud Nijmegen 503 R. Timmer, MD PhD, department of Gastroenterology, St Antonius Hospital 504 N.J. Schepers, MD, department of Gastroenterology and Hepatology, Erasmus MC 505 University Medical Center, Rotterdam 506 507 Data Safety Monitoring Committee 508 U.H.W. Beuers, MD PhD, department of Gastroenterology and Hepatology, AMC Amsterdam 509 L.P.S. Stassen, MD PhD, department of Surgery, MUMC Maastricht 510 A.H. Zwinderman, MD PhD, department of Epidemiology, AMC Amsterdam 511 R. van Hillegersberg, MD PhD, department of Surgery, UMC Utrecht 512 J.W.F.M. Bartelsman, MD PhD, Gastroenterologist 513 H.R. van Buuren, MD PhD, department of Gastroenterology and Hepatology, Erasmus MC 514 University Medical Center 515 516 Independent physician 517 V.M.C.W. Spaander, MD PhD, department of Gastroenterology and Hepatology, Erasmus 518 MC University Medical Center, 519 520 Clinical centers and principal investigators (all in the Netherlands): 521 1. Academic Medical Center University of Amsterdam, PO 22660, 1100 DD Amsterdam; JE 522 van Hooft, MD PhD, dept. of Gastroenterology; 20 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 2. Albert Schweitzer Hospital, PO 444, 3300 AK Dordrecht; W van de Vrie, MD PhD, dept. of Gastroenterology 3. Amphia Hospital Breda, PO 90158, 4800 RK Breda; M Rijk, MD PhD, dept. of Gastroenterology; 4. Canisius-Wilhelmina Hospital, PO 9015, 6500 GS Nijmegen; ACITL Tan, MD PhD, dept. of Gastroenterology; 5. Catharina Hospital, PO 1350, 5623 EJ Eindhoven; E Schoon, MD PhD, dept. of Gastroenterology; 6. Erasmus Medical Center, PO 2040, 3000 CA Rotterdam; MJ Bruno, MD PhD, professor, dept. of Gastroenterology; 7. Gelre Hospital, PO 9014, 7300 DS Apeldoorn; W Erkelens, MD PhD, dept. of Gastroenterology; 8. Hospital Gelderse Vallei, PO 9025, 6710 HN Ede; B Witteman, MD PhD, professor, dept. of Gastroenterology; 9. Jeroen Bosch Hospital, PO 90153, 5200 ME Den Bosch; TEH Römkens, MD PhD, dept. of Gastroenterology; 10. Kennemer Gasthuis, PO 417, 2000 AK Haarlem; RWM van der Hulst, MD PhD, dept of Gastroenterology; 11. Maasstad Hospital Rotterdam, PO 9100, 3007 AC Rotterdam; FJGM Kubben, MD, dept. of Gastroenterology; 12. Maastricht University Medical Center, PO 5800, 6202 AZ Maastricht; R de Ridder, MD PhD, dept. Of Gastroenterology; 13. Martini Hospital, PO 30033, 9700 RM Groningen; WJ Thijs, MD PhD, dept of Gastroenterology 14. Meander Medical Center, PO 1502, 3800 BM, Amersfoort; MP Schwartz, MD PhD, dept. of Gastroenterology; 15. Medical Center Haaglanden, PO 432, 2501 CK Den Haag; LE Perk, MD PhD, dept of Gastroenterology 21 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 16. Medisch Spectrum Twente, PO 50000, 7500 KA Enschede; NG Venneman, MD PhD, dept. of Gastroenterology; 17. OLVG Amsterdam, PO 95500, 1090 HM Amsterdam; JM Jansen, MD PhD, dept. of Gastroenterology; 18. Radboud University Nijmegen Medical Center, PO 9101, 6500 HB Nijmegen; EJM van Geenen, MD PhD, dept. of Gastroenterology; 19. Reinier de Graaf Groep Delft, PO 5011, 2600 GA Delft; CJM Bolwerk, MD PhD, dept. of Gastroenterology; 20. Rijnstate Hospital, PO 9555, 6800 TA Arnhem; BMW Spanier, MD PhD, dept. of Gastroenterology; 21. Sint Franciscus Gasthuis, PO 10900, 3004 BA Rotterdam; MGPF Anten, MD, dept. Of Gastroenterology 22. Sint Lucas Andreas Hospital, PO 9243, 1006 AE Amsterdam; SD Kuiken, MD, dept. Of Gastroenterology 23. St Antonius Hospital, PO 2500, 3430 EM Nieuwegein; R Timmer, MD PhD, dept. of Gastroenterology; 24. St. Elisabeth Hospital, PO 90151, 5000 LC Tilburg; R Laheij, MD PhD, dept. of Gastroenterology 25. University Medical Center Groningen, PO 30001, 9700 RB Groningen; HM van Dullemen, MD PhD, dept. of Gastroenterology; 26. University Medical Center Utrecht, PO 85500, 3508 GA Utrecht; FP Vleggaar, MD PhD, dept. of Gastroenterology; 27. VU University Medical Center Amsterdam, PO 7057, 1007 MB Amsterdam; F van Delft, MD, dept. of Gastroenterology. 575 576 Key staff at coordinating centers 577 AMC Amsterdam: MGH Besselink, HC van Santvoort 578 Erasmus MC University Medical Center: MJ Bruno (principal investigator), NDL Hallensleben 22 579 (coordinator), NJ Schepers (coordinator) 580 St. Antonius Hospital, Nieuwegein: S Jans (research nurse), NDL Hallensleben (coordinator), 581 NJ Schepers (coordinator) 582 UMC Utrecht, Utrecht: OJ Bakker 583 23 584 Table 1. Definitions primary end point Event Definition New-onset New-onset (i.e. not present at randomisation) and persistent (i.e. >48 hours) organ failure failure of organ(s) according to the modified Marshall score [18, 29]. Pancreatic Presence of diffuse or focal areas of pancreatic non-enhancement on contrast necrosis enhanced CT performed at 5-7 days after admission. Bacteremia Demonstrated with positive blood cultures. Blood samples will be drawn when temperature >38.5°C. For non-pathogens (e.g. Coagulase negative staphylococci) at least 2 samples have to be positive. Cholangitis Highest in-hospital body temperature in previous 24 hours: ≥ 38.5ºC with chills, without an obvious other cause (e.g., cystitis, pneumonia, thrombophlebitis, etc), or 39ºC without chills, without an obvious cause for fever, and either: 1) Choledocholithiasis on abdominal US, CT, EUS or MRI, or 2) A dilated common bile duct on imaging defined as >8mm in patients ≤75 years or >10mm in patients >75 years or 3) Progressive cholestasis for at least two consecutive days and a bilirubin >2.3 mg/dL (40 μmol/L). Pneumonia Coughing, dyspnoea, chest film showing infiltrative abnormalities, lowered arterial blood gas with positive sputum culture. If in intensive care, a positive endotracheal culture is mandatory. Exocrine Fecal elastase <200µg/g and the need for pancreatic enzyme supplementation pancreatic at 3 months after discharge; this requirement was not present before onset of insufficiency pancreatitis. Endocrine The need for insulin or oral antidiabetic drugs at 3 months after discharge; this pancreatic requirement was not present before onset of pancreatitis. insufficiency 585 24 586 Table 2. ERC related complications Event Definition Clinically relevant bleed The presence of melena, hematochezia of hematemesis, in combination with a hemoglobin drop of 1.3 mmol/L or the need for blood transfusion (defined according to the American Society for Gastrointestinal Endoscopy ASGE [39]) Perforation New development of free gas on imaging with progressive complaints of abdominal discomfort and pain after ERC, or perforation detected at surgery Respiratory insufficiency pO2<60mmHg despite FiO2 of 30% or requiring mechanical ventilation Cardiovascular complications o Acute myocardial (1) Typical rise and gradual fall (troponin) or infarction more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following: (a) ischemic symptoms; (b) development of pathologic Q-waves on the ECG; (c) ECG changes indicative of ischemia (ST segment elevation or depression); or (d) coronary artery intervention (e.g., coronary angioplasty) [40, 41]. o o Cerebrovascular Defined by the clinical event and subsequent findings on cross- accident sectional imaging investigations Shock Systolic blood pressure below 90 mmHg despite adequate fluid resuscitation or need for inotropic catecholamine support 587 25 588 Table 3. Modified Glasgow score [20] Each parameter scores 1 point. Age >55 years PO2 arterial <60 mmHg Albumine <32 g/L Total calcium <2 mmol/L Leukocytes >15 x 10 9/L LDH >600 U/L Glucose (non diabetics) >10 mmol/L Ureum after rehydration >16 mmol/L 589 26 590 Table 4. Acute Physiology and Chronic Health Evaluation (APACHE II score) [19] High abnormal Low abnormal +4 +3 Temperature (°C) ≥ 41 39.0-40.9 Mean Arterial Pressure (mmHg) ≥ 160 130-159 110-129 70-109 50-69 Heart rate ≥ 180 140-179 110-139 70-109 55-69 Respiratory rate ≥ 50 35-49 Oxygenation FiO2 ≥ 0.5, record A-aDO2 FiO2 < 0.5, record PaO2 ≥ 500 - 350-49 - Arterial pH ≥ 7.7 7.6-7.69 Serum sodium (mmol/l) ≥ 180 160-179 Serum potassium (mmol/l) ≥7 6.0-6.9 Serum creatinine (μmol/l) Double score for AKI ≥ 302 169-301 Haematocrit (%) ≥ 60 50-59.9 White blood cell count (total/mm3) ≥ 40 20-39.9 Physiological variable +2 200-349 - 155-159 +1 0 +1 +2 +3 +4 38.5-38.9 36-38.4 24-35.9 32-33.9 30-31.9 ≤ 29.9 ≤ 49 40-54 ≤ 39 ≤5 25-34 12-24 10-11 6-9 - < 200 > 70 61-70 - 55-60 ≤ 55 7.5-7.59 7.33-7.49 7.25-7.32 7.15-7.24 ≤ 7.14 150-154 130-149 120-129 111-119 ≤ 110 5.5-5.9 3.5-5.4 3-3.4 2.5-2.9 ≤ 2.4 53-124 ≤ 52 46-49.9 30-45.9 20-29.9 ≤ 19 15-19.9 3-14.9 1-2.9 ≤ 0.9 125-168 15 - Glasgow coma scale Total Acute Physiology score (APS) < 44 0 45-54 2 Age points 55-64 3 65-74 5 ≥ 75 6 APACHE-II score (sum of APS + age points + chronic health points) Chronic Health points: If the patient has a history of severe organ system insufficiency or is immunocompromised, assign points as follows: For non-operative or emergency postoperative patients, 5 points For elective postoperative patients, 2 point A-aDO2, alveolar-arterial oxygen tension difference; AKI, acute kidney injury; FiO2, fractional inspired oxygen; PaO2, arterial oxygen tension 27 591 Table 5. Definition of Chronic Pancreatitis 592 593 Chronic pancreatitis is confirmed according to the following criteria (adapted from the 594 M-ANNHEIM diagnostic criteria) [42]: 595 596 Typical clinical history of chronic pancreatitis (i.e. recurrent pancreatitis or abdominal pain), and: 597 598 One or more of the following additional criteria for the diagnosis of chronic pancreatitis: 599 Pancreatic calcifications 600 Moderate or marked ductal lesions (according to the Cambridge classification) on 601 602 MRCP, CT, or EUS Marked and persistent exocrine insufficiency defined as: 603 a) Pancreatic steatorrhea clearly relieved by enzyme supplementation, and/or 604 b) Fecal elastase levels of ≤200µg/g 605 28 606 Figure 1. Flowchart APEC trial according to CONSORT [43] All patients with acute pancreatitis Ineligible Did not meet inclusion criteria Had no biliary etiology Not at high risk for complications Had other reasons Met exclusion criteria Were admitted to the hospital >24 hours Had concomitant cholangitis Had previous sphincterotomy or precut Had symptoms for > 72 hours Had other reasons Eligible but excluded Had logistic issues Were unable to give informed consent (e.g. metal capacity, severe organ failure) Declined to participate Were transferred from other hospital >24 hours after primary admission Had other reasons 232 Patients to be randomized 116 Assigned to early ERC with sphincterotomy Received allocated treatment 116 Assigned to conservative treatment Received allocated treatment Excluded Excluded 1 Lost to follow-up 1 Lost to follow-up 115 Analyzed 115 Analyzed 607 29 608 Figure 2. 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