ChroPac-Trial: Duodenum-preserving pancreatic head resection versus pancreatoduodenectomy for chronic pancreatitis. Trial protocol of a randomised controlled multicentre trial

Chronic pancreatitis (CP) is defined as a continuous inflammatory process causing permanent structural damage ultimately resulting in impairment of the gland's exocrine and endocrine function [1, 2]. The most important causative agent is alcohol. Patients with CP who present with inflammatory pancreatic head enlargement, commonly require pancreatic head resection due to development of local complications (e. g. stenosis of the common bile duct and/or main pancreatic duct, duodenal obstruction, compression of retropancreatic vessels), suspicion of malignancy, and most commonly intractable pain [3, 4]. Pancreatoduodenectomy (PD), i.e. the classical Whipple (CW) and subsequently the pylorus-preserving Whipple (PPW) procedure has served as primary surgical procedures for removal of the pancreatic head in patients with CP and pancreatic head enlargement for many years. However, PD is reported to have unsatisfactory outcome in terms of late morbidity; including high incidence of postoperative diabetes mellitus of up to 48%, attributed to the extensive resection of the duodenum and a larger portion of the pancreas [5]. In order to preserve the duodenum and limit resection of the pancreatic tissue to a minimum, the duodenum-preserving pancreatic head resection (DPPHR) was introduced by H. G. Beger in 1972 [6, 7]. While the Beger procedure selectively removes the pancreatic head, two modifications of this procedure were developed in order to prevent dissection of the pancreas above the portal and superior mesenteric vein, a potential source of haemorrhage, particularly in case of portal hypertension: The Frey procedure consists of a local resection of the pancreatic head, which is combined with lateral pancreaticojejunostomy; in the Berne procedure the pancreatic head is resected subtotally, leaving a narrow layer of pancreatic tissue towards the duodenum and the retropancreatic vessels [4, 8, 9] (Figure 1).

A recently published randomised trial demonstrated superiority of surgical treatment (i. e. pancreaticojejunostomy) as compared with endoscopic drainage in patients with chronic pancreatitis and a distal pancreatic duct obstruction without an inflammatory mass, respectively [10]. Moreover, an up-to-date systematic review with meta-analysis indicated superiority of duodenum-preserving pancreatic head resection (DPPHR) compared with pancreatoduodenectomy (PD) in terms of several intra- (blood replacement) and postoperative (exocrine insufficiency, length of hospital stay, weight gain and occupational rehabilitation) outcome parameters as well as quality of life (QoL) [11]. However, this potential superiority of DPPHR is currently based on small hypothesis driven clinical trials performed in a single-institution setting and may be distorted by as well random error due to small sample sizes, as systematic sources of bias such as allocation concealment, standardization of study interventions, definition of outcome parameters, consistency of follow-up, and blinded outcome assessment. Large multicenter randomised trials comparing the two main strategies (DPPHR vs. PD) focussing on both the surgeons and patients perspectives are still missing.

ChroPac aims to investigate differences in QoL during 24 months after surgery of DPPHR versus PD and mortality as well as general and pancreas-associated postoperative morbidity.

ChroPac will be performed in thirteen trial sites with expertise for pancreatic surgery. Most of the participants were involved in a former multicentre-trial surgical trial for pancreatic left resection (DISPACT Trial, ISRCTN 18452029) carried out by the Study Centre of the German Surgical Society (SDGC). Thus the ChroPac trial group consists of international pancreatic surgeons at high-volume centres who also have expertise in trial conduction.

All patients scheduled for primary elective surgery for chronic head-pancreatitis will be eligible, assuming their ability to understand the character and individual consequences of participation as well as written informed consent. Patients participating in another interventional trial with potential interference of intervention (e.g. trials evaluating alternative perioperative analgetic regimens, application of octreotide etc.) and outcome (e.g. trials focussing on QoL) will be excluded.

A total of 200 patients will be randomised and included in the analysis.

Randomised, controlled, observer and patient blinded multicentre surgical trial with two parallel comparison groups.

13 centres with high-level expertise for pancreatic surgery will contribute to recruitment of study patients. The duration of the trial for each participant is expected to be about 2 years. The duration of the overall trial is expected to be 5 years, including prearrangement and analysis. Recruitment of participants started in April 2009. The process of the trial conduct is illustrated in Figure 2.

In order to achieve comparable intervention-groups, patients will be allocated concealed by preoperative randomisation at the day of surgery using a centralised web based tool http://​www.​randomizer.​at. Block randomisation will be performed for each centre to achieve equal group sizes per centre.

Patients and outcome assessors will be blinded for the trial intervention.

No additional risks for study patients are awaited, since all surgical procedures carried out within ChroPac represent clinically established standard methods of treatment of chronic pancreatitis.

The primary outcome measure of this trial is the average QoL during 24 months after surgery, measured 6, 12 and 24 months after surgery by the EORTC QLQ-C30 scale „physical functioning“ (PF-2). Secondary outcomes of: mortality, general (wound infection, pulmonary infection) and pancreas-associated postoperative morbidity (pancreatic fistula, delayed gastric emptying), operation time, intraoperative blood loss, initial postoperative hospital stay, reoperation, hospital stay related due to chronic pancreatitis within 24 months after randomisation, weight gain, development of exocrine insufficiency and new onset of diabetes mellitus will be assessed (Table 2). All outcome variables will be evaluated according to internationally accepted standards and scoring systems if available, i.e. the consensus definitions for pancreatic fistula and delayed gastric emptying of the International Study Group of Pancreatic Surgery (ISGPS) [12, 13].

All protocol-required information for the clinical data collected during the trial must be entered by the investigator, or by a designated representative, in the eCRF. The investigator is responsible for ensuring that all sections of the eCRF are completed correctly and that entries can be verified against source data. Any entry and correction in the Remote Data Entry System will be recorded automatically in an audit file. Once the documentation of a patient is completed and checked for plausibility the investigator is asked to date and sign it via electronic identification. Documentation of quality of life questionnaires will be done on paperbased CRFs.

Double data entry will be accomplished in order to ensure completeness, validity and plausibility of trial data.

Analysis of safety related data is performed with respect to frequency of serious adverse events, frequency of serious adverse events stratified by causality and frequency of morbidity in both treatment groups.

From the day the patient has signed informed consent until the regular end of trial at 24 months follow-up or until premature withdrawal of the patient, all serious adverse events will be documented on a "serious adverse event form" available in the investigator site file. A serious adverse event will be defined as an event, that results in death, is immediately life-threatening, requires or prolongs hospitalization or results in persistent or significant disability or incapacity. Serious adverse events will be classified to intensity (mild, moderate, severe), outcome (ongoing, recovered completely, recovered with sequelae, death, unknown) and causality (unrelated; possibly, probably or definitely related to trial intervention; not assessable). The assessment is based on surgical findings and the clinical course of the patient. It needs to be done by the investigators in the participating trial centres. They will be furnished with written recommendations on how to assess causality with trial intervention within the ChroPac trial.

Serious adverse events have to be reported by the attending physician to the principal investigator within 24 hours after the SAE becomes known.

Patients are free to withdraw trial participation at their own request at any time and without giving reasons for their decision. Moreover, the primary investigator can withdraw study patients, if continuation of the trial would be detrimental to the patient's well being.

Withdrawals will be documented in the CRF and in the patient's medical records and all ongoing serious adverse events have to be followed up.

In case of any irregularities for example concerning the frequency or type of serious adverse events reported the principal investigator will inform the members of the independent DSMB without delay. At least once every 12 months, the DSMB will receive a written safety report. The result of the risk/benefit assessment will be reported to the principal investigator including recommendations concerning the continuation of the trial (Members of the DSMB: Gabriele Ihorst, PhD, Centre for Clinical Trials, University of Freiburg, Germany; Pierluigi Di Sebastiano, MD, Director General Surgery, San Giovanni Rotondo, Foggia, Italy; Helmut Witzigmann, Director Surgical Department Friedrichstadt Hospital, Dresden, Germany).

No interim analysis is planned for ChroPac. The trial can be prematurely closed by the coordinating investigator in consultation with the steering committee, the Data Safety Monitoring Board and the responsible biometrician for the following reasons:

In case of premature closure, the ethics committee has to be informed.

The basic and clinical research aims to identify parameters which influence the clinical outcome and may be useful for prognostic or therapeutical decision making in future with main focus on differences between the two surgical techniques (DPPHR vs. PPW). Serum parameters (20 ml blood) are investigated and pancreatic tissue is analysed by histology, as well as biochemical and molecular biological techniques in a standardised fashion. The molecular alterations are analysed in detail and assessed for its clinical implications. Important parameters of pancreatic tissue in chronic pancreatitis include inflammation and fibrosis and the correlation to pain and pain relief: standardised histological reporting of the degree of inflammation and fibrosis, identification and quantification of expression of pancreatic enzyme activation (e.g. trypsin), cytokines, chemokines, growth factors (e.g. EGFR, TGF), stellate cells and its mediators, collagens are performed.

Since pain is the most frequent indication for pancreatic surgery, a main focus is the investigation of pancreatic and peripancreatic nerves, neurotransmitter, nerve growth factors, and the correlation of pain, chronic inflammation and its relief by pancreatic resection. Potential markers include substance P, NK-1R, CGRP, VIP, NPY, PACAP, bradykinine, eicosanoids. Diabetes mellitus (endocrine insufficiency) has major impact on the long-term outcome of patients with chronic pancreatitis. The correlation of endocrine insufficiency and reduction of endocrine cells and products (insulin, glucagons) in chronic pancreatitis are investigated. Chronic pancreatitis is a known risk factor for pancreatic cancer and premalignant lesions can be detected in inflammatory disease. Serum and tissue markers of carcinogenesis including K-ras, p-53 will be investigated and correlated with histology, clinical outcome, and surgical techniques used. All investigations will be performed centralised and all data stored in a separate database. This will be linked to the clinical database to answer the above-mentioned questions.

The research question of ChroPac is based on sufficient pilot data and since further single centre studies would not be able to strength the external validity, only a multicentre trial can demonstrate the superiority of DPPHR compared with PD in a setting close to daily practice. The Study Centre of the German Surgical Society (SDGC) as the coordinating organisation is experienced and has a proven track record in performing multicentre surgical trials, which highlight the SDGC's central role in trial design and administration and only go to strengthen the feasibility of the proposed trial [18]. An investigators meeting, which was conducted prior to the randomisation of the first patient represents strength of the ChroPac trial: 15 participants of the recruiting departments met at the SDGC in Heidelberg, Germany for a two day educational and practical workshop. While focussing on the explanation of the trials' rationale, surgical procedures, ethics, data management and monitoring within ChroPac, all participants attended surgical procedures for chronic pancreatitis on the second day at the operation theatres at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany. Overall, the theoretical as well as the hands-on surgical training was highly appreciated and well-rated by the participants (range 1.3 - 2.6 with possible grades from 1 to 6). Moreover, there was general agreement regarding the rationale of the trial, primary outcome measure and feasibility of the trial (range 1.5 - 1.9 with possible grades from 1 to 4). As a result content, comprehensiveness and learning effect was rated to be excellent/very good (range 1.5 - 1.6 with possible grades from 1 to 6). Consequently, ChroPac promises optimal recruitment of study patients with good data quality by a both expertise and conform trial group.

However, the design of ChroPac raised some discussion during the design phase:

Secondly, the specific trial design was a matter of debate. Since RCTs can be performed as efficacy (or explanatory) as well as effectiveness (or pragmatic) trials, the question to focus on internal validity (generation of the allocation sequence; allocation concealment; blinding; intention to treat analysis; complete outcome reporting and follow-up etc.) or on external validity (generalisability) was of major importance. Thus, performing an efficacy trial promises distinct evaluation of two surgical procedures rather than surgical strategies. ChroPac as an efficacy trial would have required explicitly defined surgical procedures (e.g. Frey versus PPW) and study patients. However, patients' compliance and generalisability is known to be low in these study designs and four single RCTs are already available [19, 20]. As a result of the discussions during the investigator meeting the participants agreed and support the pragmatic approach of ChroPac:

Firstly, the available systematic review showed that the comparison of duodenum-preserving techniques versus pancreatoduodenectomy is currently hampered by the methodological weakness of only small available RCTs. Secondly, focussing on a sufficient sample size and optimal data quality the pragmatic approach with compact trial data acquisition and reduced study visits accounts for the compliance of both the investigators and the participating study patients. Thirdly, even a pragmatic approach allows a translational research part for further investigations of nature and mechanisms of chronic pancreatitis. Moreover, ChroPac evaluates a complex intervention and has to consider the expertise of different surgeons, peri-operative treatment regimens and concomitant interventions. Since these varying components reflect the current state-of-the-art treatment of chronic pancreatitis in centres of excellence for pancreatic surgery, ChroPac provides the most efficient evaluation of the present standard.

In summary, the ChroPac-Trial was designed to identify the best surgical strategy for treatment of chronic pancreatitis-either duodenum-preserving head resection or pancreatoduodenectomy. Focussing on a comparison of a general surgical strategy implies that the ChroPac-Trial will not be able to identify the best specific surgical technique in terms of available modifications of either PD or DPPHR. The aim of the ChroPac-Trial was therefore to maximize external validity while sustaining acceptable internal validity, which was accomplished by its pragmatic approach [21].