Ward-based Goal-Directed Fluid Therapy (GDFT) in Acute Pancreatitis (GAP) trial: study protocol for a feasibility randomised controlled trial

Introduction Acute pancreatitis is an inflammatory disease of the pancreas with high risk of developing multiorgan failure and death. There are no effective pharmacological interventions used in current clinical practice. Maintaining fluid and electrolyte balance is the mainstay of supportive management. Goal-directed fluid therapy (GDFT) has been shown to decrease morbidity and mortality in surgical conditions with systemic inflammatory response. There is currently no randomised controlled trial (RCT) investigating the role of GDFT based on cardiac output parameters in patients with acute pancreatitis in the ward setting. A feasibility trial was designed to determine patient and clinician support for recruitment into an RCT of ward-based GDFT in acute pancreatitis, adherence to a GDFT protocol, safety, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate efficacy. Methods and analysis The GDFT in Acute Pancreatitis trial is a prospective two-centre feasibility RCT. Eligible adults admitted with new onset of acute pancreatitis will be enrolled and randomised into ward-based GDFT (n=25) or standard fluid therapy (n=25) within 6 hours from the diagnosis and continuing for the following 48 hours. Cardiac output parameters will be monitored with a non-invasive device (Cheetah NICOM; Cheetah Medical). The intervention group will consist of a protocolised GDFT approach consisting of stroke volume optimisation with crystalloid fluid boluses, while the control group will receive standard care fluid therapy as advised by the clinical team. The primary endpoint is feasibility. Secondary endpoints will include safety of the intervention, complications, mortality, admission to intensive care unit, cost and quality of life. Ethics and dissemination Ethics approval was granted by the London Central Research Ethics Committee (17/LO/1235, project ID: 221872). The results of this trial will be presented to international conference with interest in general surgery and acute care and published in a peer-reviewed journal. Trial registration number ISRCTN36077283.

211 Blinding 212 It will not be possible to blind the research or clinical team during the first 48 hours of the 213 study. However, the participants, outcome assessors of health-related quality of life, and 214 statisticians will be blinded to the groups. Patient blinding will be aided by NICOM monitoring 215 of both intervention and control groups but performing GDFT in the intervention group alone.
216 NICOM data from the control group will be collected at the same time points as the intervention 217 group and will not be available to the treating clinicians.
218 219 Outcome measures 220 The primary outcome of the trial will be an assessment of feasibility. In particular, the ability to 221 identify and recruit patients at the selected sites to a study of acute pancreatitis. A recruitment 222 rate of at least 30% over 17-month trial period will be deemed as successful. We will also 223 assess the availability of study team for a condition presenting as an emergency, ability to 224 randomise and commence ward GDFT within 6 hours of admission, completion rate of 48 225 hours of GDFT, rate of withdrawal (less than 20%) from GDFT protocol, reasons for withdrawal 226 from GDFT protocol and proportion of complications in the two groups.

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228 Several secondary clinical, surgical, biochemical, safety and quality of life outcomes will also 229 be collected. Mortality will be assessed as well. Clinical outcomes will include severity of 230 pancreatitis as assessed by Glasgow score, proportion of patients with severe acute 231 pancreatitis, necrotising pancreatitis, infected pancreatic necrosis, requiring ITU stay, 232 requiring renal replacement therapy, requiring ventilation, requiring surgical interventions for 233 complications related to pancreatitis and incidence of positive blood cultures. Resource use 234 data for health economic analysis on length of hospital stay, length of ICU stay, and number 235 of days ventilated, time to return to pre-pancreatitis activities, number of work days lost (in 236 those who work), and costs (NHS and personal social services (PSS) perspectives) will be 237 collected. Health-related quality of life (HRQoL) will be assessed using the well validated 241 serious adverse events related to intervention will be recorded up to discharge and at follow-242 up. Routine biochemical tests performed as part of clinical care including blood gases, liver 243 function tests, clotting profile, renal function, amylase, full blood count and C-reactive protein 244 (CRP) will be recorded on admission and daily up to two weeks and bi-weekly up to discharge.
245 In addition, serum samples will be collected from participants in both groups on admission, 246 12, 24-and 48-hour time points and stored at -80 degrees for future analysis of biomarkers in 247 acute pancreatitis.

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249 Follow-up 250 Participants will be followed for 90 days. All clinical and HRQoL outcomes will be measured 251 up to discharge and specifically at 30 days and 90 days by face-to-face or telephone follow-252 up. CRP will be measured at 24 hours and 48 hours and every 24 hours during the hospital 253 stay as per routine clinical practice.

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Since this is a feasibility study, all analyses other than recruitment rate and withdrawal rates 285 should be considered exploratory. The two groups will be compared to ensure they have 286 similar baseline characteristics (table 3)    12 294 between the two groups will be presented and compared using appropriate statistical test and 295 95% confidence interval. 296 297 For the secondary outcomes, amongst patients who participate in the trial, all clinical and 298 surgical outcome measures will be presented for each group separately using the mean, 299 standard deviation, median, minimum and maximum for continuous outcomes and using 300 frequencies and proportions for categorical variables.

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Quality of life will also be summarised for each group using mean profile plots over time. The 303 mean difference in quality of life scores between the two groups at 7 days up will be presented 304 with a 95% confidence interval.

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306 Kaplan-Meier survival estimates and plots will be presented to compare survival rates between 307 the two groups. 308 309 All other secondary outcomes collected over time will be summarised for each group using 310 mean profile plots. Mean differences for continuous outcomes and difference in proportion for 311 binary outcomes shall be presented, with appropriate 95% confidence intervals, at 30 and 90 312 days.

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The number and nature of adverse events shall be reported for each group. No formal 315 comparisons between the groups will be made and no hypothesis tests will be carried out. The 316 results will inform us how sensitive the outcome measures are and, along with other 317 information, will be used to determine the primary outcome of a subsequent large RCT. The 318 results will also inform a sample size calculation for the primary outcome chosen.  13 321 This is a feasibility study and one aspect of this feasibility evaluation is the ability to recruit 322 patients with acute pancreatitis into a trial of this nature. According to hospital episode 323 statistics, an in-house review of admissions for acute pancreatitis to the Royal Free Hospital 324 over the last three years showed 107 cases per year. After excluding patients who were 325 transferred from another hospital for tertiary care, those who required immediate ICU 326 admission, those with chronic pancreatitis in whom an acute exacerbation could not be 327 confirmed by internal consensus criteria, current or past cardiac failure, or unable to provide 328 fully informed consent, 80 patients per year would be eligible for this trial from a single centre.
329 With a second centre we would anticipate 120 suitable patients per year. We anticipate 330 recruiting at least 30% of potential participants which equates to 36 participants annually and 331 a recruitment time of 17 months to recruit the 50 patients.

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333 For feasibility assessment, a recruitment log will be used to collect information on suitability 334 and consent rate as well as availability of trials team for GDFT, consent, failure to commence 335 ward GDFT, withdrawal with reasons and failure to complete the study. In case of lower than 336 anticipated recruitment at six months, we will perform the following; a) analyse the results of 337 the qualitative research earlier and identify the reasons for poor recruitment (and take actions 338 to resolve the problems) if we get the anticipated number of patients screened but the 339 recruitment rate is lower than anticipated, b) recruitment of additional centres if we do not get 340 the anticipated number of potential participants screened but the recruitment rate is at least 341 as good as the anticipated rate c) a combination of the above if the number of potential 342 participants screened and the recruitment rate are lower than anticipated. 343 344 We will explore the reasons for participation and non-participation of eligible patients and 345 patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment 346 strategies employed for the definitive trial. Non-participation can be related to how the clinical 347 trial is presented to the patient, and how the patient assimilates this information. It is therefore 348 important to understand how patients perceive information about potential participation and 349 their experiences of receiving information relating to the trial. Interviews with a sample of 350 eligible patients will explore patient perspectives of treatment, their understanding of the two 351 treatments, reasons for taking part or refusing the trial, and the acceptability of randomisation 352 between the procedures. Interviews with clinical staff will explore their views about the trial, 353 clinical equipoise, and their understanding of the recruitment challenges. Semi-structured 354 interviews will be informed by a topic guide developed in conjunction with the trial management 355 group which includes patient representatives. Patient information sessions (recruiter 356 meetings) will be audio recorded to examine how information is presented, and identify issues 357 potentially affecting trial recruitment. Patient information sessions will be analysed at an early 358 stage if there is poor recruitment and will inform the development of any additional training 359 materials for recruitment for the definitive trial. 360 361 Progress to full trial 362 The criteria to progress to a subsequent full trial will be determined quantitatively as a) consent 363 rate of at least 30%, the ability to recruit 50 patients to the study at the two sites over 17 364 months, b) GDFT can be successfully performed within 6 hours of diagnosis of acute 365 pancreatitis and can be continued until at least 48 hours after admission in a minimum of 80% 366 of participants randomised to GDFT, and c) the complication rate in the intervention group is 367 not more than 10% higher than that of the control group at 90 days. A cut off of 30% has been 368 chosen for recruitment as this would be an achievable target in the definitive trial. A lower 369 recruitment rate may indicate a lack of acceptability among clinicians and/or patients to 370 participate in the definitive trial. In addition, a recruitment rate less than 30% is likely to make 371 the subsequent definitive trial very expensive. A less than 30% recruitment may also highlight 372 issues related to generalisability of the results, indicating a reduction in value of the 373 subsequent definitive trial in terms of applicability in NHS. The results of this study will be presented to the national and international meetings with 377 interest in the management of acute pancreatitis and prepared for publication in peer-378 reviewed journals with a readership in general surgery and critical care.

380 Discussion
381 Acute pancreatitis is an inflammatory disease associated with a high mortality rate (23).

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In your methods section, say that you used the SPIRIT reporting guidelines, and cite them as:        1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59    103 lack of information on the optimal fluid therapy in acute pancreatitis (9,10). There has also 104 been a decline in research in treatments for acute pancreatitis in general (11).    146 The GAP trial has been designed in accordance with the SPIRIT guidelines as a two centre, 147 feasibility RCT (18). The study will primarily investigate the ability to recruit patients at the 148 selected sites to a feasibility RCT of ward-based GDFT versus standard fluid therapy in 149 patients with acute pancreatitis, the rate of withdrawal from GDFT protocol, and the reasons 150 for withdrawal from GDFT protocol. We will also assess the safety and practicality of ward-151 based GDFT and collect outcome measures which can be evaluated as end points for a 152 subsequent multi-centre study on efficacy. Indicative costs will be collected to inform a 153 subsequent cost effectiveness study. The trial outline is illustrated in Figure 1 and the schedule 154 of enrolment, interventions and assessments is shown in Table 1. 168 summarised and abbreviated patient information sheet (PIS) will be provided for patients 169 initially on arrival and they will be subsequently provided with an in-depth version. Informed

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178 Randomisation 179 This will be performed using 'Sealed Envelope', an internet-based randomisation system 180 (www.sealedenvolpe.com). Eligible patients who have consented to take part in the trial will 181 be 1:1 randomised to ward based GDFT or standard care, stratified by site on admission, prior 182 to ward transfer. The trial research nurse responsible (unblinded) will log into the database 183 and create randomisation codes for both groups online. Information on randomisation will be 184 stored in the case report form (CRF).   219 statisticians will be blinded to the groups. Patient blinding will be aided by NICOM monitoring 220 of both intervention and control groups but performing GDFT in the intervention group alone.
221 NICOM data from the control group will be collected at the same time points as the intervention 222 group and will not be available to the treating clinicians.

224 Outcome measures
225 The primary outcome of the trial will be an assessment of feasibility. In particular, the ability to 226 identify and recruit patients at the selected sites to a study of acute pancreatitis. A recruitment 227 rate of at least 30% over 17-month trial period will be deemed as successful. We will also 228 assess the availability of study team for a condition presenting as an emergency, ability to 229 randomise and commence ward GDFT within 6 hours of admission, completion rate of 48 230 hours of GDFT, rate of withdrawal (less than 20%) from GDFT protocol, reasons for withdrawal 231 from GDFT protocol and proportion of complications in the two groups.

232
233 Several secondary clinical, surgical, biochemical, safety and quality of life outcomes will also 234 be collected. Mortality will be assessed as well.    282 We wish to thank our patient representatives for their contribution and participation in this process.

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355 For feasibility assessment, a recruitment log will be used to collect information on suitability 356 and consent rate as well as availability of trials team for GDFT, consent, failure to commence 357 ward GDFT, withdrawal with reasons and failure to complete the study. In case of lower than 358 anticipated recruitment at six months, we will perform the following; a) analyse the results of        Patients are screened by the medical and surgical team in the emergency department for eligibility and referred for consent and registration. The trial nurse or surgical team provide trial patient information sheets (abbreviated and full versions) and gain informed consent. Trial nurses then randomise the patient to either GDFT or standard care and commence NICOM monitoring for 48 hours. Follow-up will be at the point of discharge, 30 days and 90 days.

Figure 2. Goal-directed fluid therapy (intervention) protocol
Flow diagram of SV optimisation with maintenance fluid administration. Patients randomised to GDFT will receive a 1.5ml/kg/hr of intravenous crystalloid maintenance fluid and four hourly visits from the trial nurses. At the first 4-hour visit, a bolus of 250mL crystalloid over 5-10mins will be administered. A SV rise of >10% would indicate fluid responsiveness and a further cycle of fluid bolus is administered until there is no SV rise >10%. At the next 4 hourly visit if SV has dropped by >10% the cycle is repeated.

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230 Outcome measures
231 The primary outcome of the trial will be an assessment of feasibility. In particular, the ability to 232 identify and recruit patients at the selected sites to a study of acute pancreatitis. A recruitment 233 rate of at least 30% over 17-month trial period will be deemed as successful. We will also 234 assess the availability of study team for a condition presenting as an emergency, ability to 235 randomise and commence ward GDFT within 6 hours of admission, completion rate of 48 236 hours of GDFT, rate of withdrawal (less than 20%) from GDFT protocol, reasons for withdrawal 237 from GDFT protocol and proportion of complications in the two groups. Although the study is 238 not powered to show differences in haemodynamic variables, we will analyse the 239 haemodynamic data (such as SV and CO) at the end of the trial for patients in both groups to,   294 We wish to thank our patient representatives for their contribution and participation in this process.

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In your methods section, say that you used the SPIRIT reporting guidelines, and cite them as: Chan Participant timeline #13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) Table 1 Sample size #14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations 10 Recruitment #15 Strategies for achieving adequate participant enrolment to reach target sample size 7 Allocation: sequence generation #16a Method of generating the allocation sequence (eg, computergenerated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 7 Allocation concealment mechanism #16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 7 Allocation: implementation #16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 7 Blinding (masking) #17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how 9 Blinding (masking): #17b If blinded, circumstances under which unblinding is permissible, 9  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60