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Pancreatic resection with perioperative drug repurposing of propranolol and etodolac – trial protocol of the phase II randomized placebo-controlled PROSPER-trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-040406

Article Type: Protocol

Date Submitted by the 12-May-2020 Author:

Complete List of Authors: Hüttner, Felix; University of Heidelberg, Department of General, Visceral and Transplantation Surgery; University of Heidelberg, The Study Center of the German Surgical Society (SDGC) Rooman, Ilse; The Anticancer Fund; Vrije Universiteit Brussel, Laboratory of Medical and Molecular Oncology Bouche, Gauthier; The Anticancer Fund Knebel, Phillip; UniversitatsKlinikum Heidelberg, Department of General, Visceral and Transplantation Surgery Hüsing, Johannes; Heidelberg University, Coordination Center for Clinical Trials Mihaljevic, A; UniversitätsKlinikum Heidelberg, Thilo, Hackert; Heidelberg University, Department of General, Visceral and Transplantation Surgery http://bmjopen.bmj.com/ Strobel, Oliver ; Heidelberg University, Department of General, Visceral and Transplantation Surgery Buchler, Markus W.; Heidelberg University, Department of General, Visceral and Transplantation Surgery Diener, M. K.; Heidelberg University, Department of General, Visceral and Transplantation Surgery

Gastrointestinal tumours < ONCOLOGY, Adult oncology < ONCOLOGY, Keywords: Pancreatic surgery < SURGERY on September 28, 2021 by guest. Protected copyright.

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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Pancreatic resection with perioperative drug repurposing of propranolol and etodolac – trial BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 protocol of the phase II randomized placebo-controlled PROSPER-trial 6 7 8 Felix J. Hüttner1,2, Ilse Rooman3,4, Gauthier Bouche3, Phillip Knebel1, Johannes Hüsing5, André L. 9 Mihaljevic1, Thilo Hackert1, Oliver Strobel1, Markus W Büchler1*, Markus K. Diener1,2 10 11 12 1Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany 13 14 2The Study Center of the German Surgical Society (SDGC), University of Heidelberg, Heidelberg, Germany 15 3The Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium 16 17 4Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussels, Belgium 18 5Coordination Center forFor Clinical Trials,peer University review of Heidelberg, Heidelberg, only Germany 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 *Correspondence to: Prof. Dr. Markus W. Büchler, Department of General, Visceral and Transplantation 42 43 Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany; email: 44 [email protected]; phone: +49 (0) 6221 / 56-6112 45 on September 28, 2021 by guest. Protected copyright. 46 47 Word count: 4142 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Introduction 6 Pancreatic cancer is the fourth most frequent cause of cancer-related deaths in developed countries. 7 8 Despite major advances in systemic chemotherapy in recent years, the mainstay of curatively intended 9 therapy for non-metastatic disease is surgical resection. However, the perioperative period is 10 11 characterized by stress and inflammatory reactions that can contribute to metastatic spread and disease 12 13 recurrence. Catecholamines and prostaglandins play a crucial role in these stress reactions and 14 inflammatory responses. Therefore, a drug repurposing of betablockers and cyclooxygenase inhibitors 15 16 during the perioperative period seems reasonable to effectively attenuate tumor-associated inflammation 17 by inhibiting psychological, surgical and inflammatory stress responses. These mechanisms may cause 18 For peer review only 19 a relevant antitumorigenic and antimetastatic effect during the perioperative period, a window for 20 cancer-directed therapy that is currently largely unexploited. 21 22 23 24 Methods and analysis 25 This is a prospective, single-center, two-arm randomized, patient and observer blinded, placebo- 26 27 controlled, phase-2 trial to evaluate safety and feasibility of combined perioperative treatment with 28 propranolol and etodolac in patients with cancer of the pancreatic head undergoing elective 29 30 pancreatoduodenectomy. A total of 100 patients fulfilling the inclusion criteria will be randomized to 31 32 perioperative treatment from 10 days preoperatively until postoperative day 14 with a combination of 33 propranolol and etodolac or correlating placebo. Patients will be followed-up regarding safety aspects 34 35 for 3 months postoperatively and for 24 months for survival and recurrence. The clinical trial is 36 accompanied by a translational study investigating the mechanisms of action of the combined therapy 37 http://bmjopen.bmj.com/ 38 on a molecular basis. 39 40 41 Ethics and dissemination 42 43 The PROSPER-trial has been approved by the German Federal Institute for Drugs and Medical Devices 44 (reference number 4042875) and the Ethics Committee of the Medical Faculty of the University of 45 on September 28, 2021 by guest. Protected copyright. 46 Heidelberg (reference number AFmo-385/2018). The final trial results will be published in a peer 47 reviewed journal and will be presented at appropriate national and international conferences. 48 49 50 51 Trial registration number 52 DRKS00014054; EudraCT number: 2018-000415-25 53 54 55 56 57 58 59 60

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1 2 3 Strengths and limitations of this study BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 - This is the first clinical trial assessing a combined treatment with a betablocker (propranolol) 6 and a cyclooxygenase inhibitor (etodolac) in the perioperative period surrounding partial 7 8 pancreatoduodenectomy for cancer of the pancreatic head. 9 10 - Strengths of this study are its randomized, double-blind, placebo-controlled design and its 11 transparent design with the clear definitions of endpoints. 12 13 - A potential limitation may be the limited sample size and broad exclusion criteria, which may 14 limit generalizability of the data. 15 16 - If the trial treatment proves to be safe, the perioperative period may be used as a window for 17 cancer-directed therapy and the results will form the basis for a subsequent phase III trial. 18 For peer review only 19 20 21 INTRODUCTION 22 More than 450,000 new cases of pancreatic cancer are diagnosed worldwide per year.1 In contrast to 23 24 many other cancers, its incidence and mortality have been rising during the last decades and the 25 prognosis is devastating with a 5-year overall survival of < 10%.2 3 Despite substantial advancements in 26 27 systemic chemotherapy during recent years, the mainstay of curatively intended treatment remains 28 29 surgical resection. However, only a small proportion of patients present with potentially resectable 30 disease (primary resectable or borderline resectable) at diagnosis.4 With modern multimodal treatment 31 32 strategies consisting of resection and adjuvant chemotherapy, a median overall survival of 54 months 33 can be reached, but disease-free survival at three years is still < 50% in these patients.5 34 35 For patients with potentially resectable tumors, the perioperative time period, which spans an 36 interval from the timepoint of diagnosis until the actual start of adjuvant chemotherapy, 37 http://bmjopen.bmj.com/ 38 represents a window of opportunity for perioperative therapy aimed to reduce recurrence.6 The 39 40 psychological stress and the emotions around diagnosis, surgery and upcoming chemotherapy 41 are accompanied by increased release of catecholamines exerting their effects on tumor cells 42 43 and stromal cells that express adrenergic receptors. These stress responses are pro- 44 tumorigenic with pleiotropic effects on the primary tumor, the tumor microenvironment, 45 on September 28, 2021 by guest. Protected copyright. 46 malignant cells in the circulation and on pre-existing micrometastases.7 Interestingly, the 47 48 effects of catecholamines may be counteracted by adrenergic receptor antagonists (beta- 49 blockers), often prescribed for hypertension or cardiac disease. 50 51 Surgically induced inflammation and the subsequent release of prostaglandins are additional 52 mediators of tumorigenic and pro-metastatic effects in the perioperative period.8 53 54 Prostaglandins facilitate tumor cell survival, proliferation and invasion and also counteract 55 immunosurveillance.9-11 Prostaglandins promote angiogenesis and epithelial-mesenchymal 56 57 transition and they lead to a release of pro-survival and growth factors for malignant cells.7 8 In 58 59 addition, prostaglandins promote microvascular barrier dysfunction, endothelial 60 hyperpermeability and lymphatic dilation, which can facilitate lymphatic and distant

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1 2 3 metastases.12-14 Prostaglandin synthesis from arachidonic acid involves the cyclooxygenases BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 (COX), of which COX-2 is the inducible form that is particularly active during inflammation by 6 generating prostaglandin E2 (PGE-2). COX are druggable targets and the above-mentioned 7 8 effects could be counteracted by selective COX-2 inhibitors. 9 The term ‘drug repurposing’ describes an approach trying to repurpose well-characterized drugs in a 10 11 novel intent. This emerging strategy is of particular interest for oncologic purposes.15 16 In terms of drug 12 13 repurposing a combination therapy of propranolol, a non-selective beta-blocker, and etodolac, a COX- 14 2- inhibitor, in the perioperative setting surrounding resection of pancreatic cancer promises an effective 15 16 attenuation of tumor-associated inflammation by inhibiting psychological, surgical and inflammatory 17 stress responses.17 By these mechanisms, it may cause a relevant antitumorigenic and antimetastatic 18 For peer review only 19 effect during the perioperative period, which is a window for cancer-directed therapy that is currently 20 largely unexploited. Since this will be the first clinical trial to assess the combination therapy of 21 22 propranolol and etodolac in the perioperative setting of pancreatic cancer, safety will be the main 23 24 outcome of interest. Beyond safety, feasibility must be analyzed, since the two predominant factors 25 (surgery and adjuvant chemotherapy) for curative treatment must not be affected by the above- 26 27 mentioned drug administration. 28 29 30 METHODS AND ANALYSIS 31 32 Study design 33 The PROSPER-trial is a two-arm randomized, patient and observer blinded, placebo-controlled, phase-2 34 35 trial. The primary objective is to evaluate safety and feasibility of perioperative propranolol and etodolac 36 treatment in patients with resectable cancer of the pancreatic head planned for elective 37 http://bmjopen.bmj.com/ 38 pancreatoduodenectomy. Additionally, early parameters of efficacy will be assessed by analyzing 39 survival of the patients and by an ancillary translational study investigating the mechanisms of action of 40 41 the combined therapy on a molecular basis. The trial will be performed in a single-center setting at the 42 43 Department of General, Visceral and Transplantation Surgery of the University Hospital Heidelberg, 44 Germany, a center of excellence for pancreatic surgery with high volume in oncologic pancreatic 45 on September 28, 2021 by guest. Protected copyright. 46 surgery. Before inclusion of the first subject, the trial was registered with the German Clinical Trials 47 Register (DRKS00014054). The full protocol and the current protocol publication were prepared in line 48 49 with the SPIRIT recommendations (Standard Protocol Items: Recommendations for Interventional

50 18 51 Trials). 52 The two drugs under investigation, propranolol and etodolac, will be repurposed in the perioperative 53 54 setting of patients undergoing elective pancreatic head resection in order to potentially improve 55 oncological outcome by suppressing several pathways of systemic stress and inflammatory responses. 56 57 Eligible patients, who have provided written informed consent, will be randomized to either the 58 combined drug therapy with propranolol and etodolac, starting 10 days preoperatively until 59 60 postoperative day 14, or corresponding placebo treatment. Pancreatic resection and postoperative care

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1 2 3 will be performed according to local standards of the Department of General, Visceral and BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 19 5 Transplantation Surgery of the University Hospital Heidelberg. 6 7 8 Study population and eligibility criteria 9 Patients with malignancy of the pancreatic head scheduled for elective pancreatoduodenectomy in 10 11 curative intent will be consecutively screened for eligibility according to the inclusion and exclusion 12 13 criteria that are listed in Box 1. Eligible patients will be informed verbally and in writing in 14 comprehensible language about the nature, scope and possible consequences of the trial by a trial 15 16 investigator. If a patient has provided written informed consent for trial participation (s)he will be 17 randomized to the verum or placebo group. Ineligible patients and those who refused to participate will 18 For peer review only 19 be documented in a screening log with the respective reason for non-participation. 20 21 22 Box 1. Major eligibility criteria of the trial 23 24 Inclusion criteria: 25 26 - Resectable malignancy of the pancreatic head, eligible for elective pancreatoduodenectomy 27 in curative intent 28 - WHO / ECOG performance status 0-2 29 30 - Age ≥ 18 years 31 32 - ASA score I-III 33 - Patient must be able to understand the consequences of trial participation and to provide 34 written informed consent 35 36 - Written informed consent from the trial subject has been obtained 37 - Female subject must be postmenopausal (for at least 6 months), surgically sterile, abstinent, http://bmjopen.bmj.com/ 38 or, if sexually active, be practicing an effective method of birth control (e.g., prescription of 39 oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, 40 contraceptive patch, male partner sterilization) before entry and throughout the study; and 41 have a negative serum ß-hCG pregnancy test at screening 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 Exclusion criteria: 47 48 - Any contraindication for pancreatoduodenectomy 49 - Metastatic disease (Stage IV) 50 51 - Patients scheduled for palliative resection (no curative treatment intention) 52 - Patients scheduled for extended resections (i.e. arterial resections, planned multivisceral 53 resections) 54 55 - Acute or ongoing episode of cholangitis: fever and pain in the right upper quadrant of the 56 abdomen together with increased infectious parameters and elevated AP & GGT values 57 (alkaline phosphatase, gamma glutamyl transpeptidase) > 3x upper limit of norm (ULN) 58 59 - Acute or ongoing episode of pancreatitis (clinical symptoms of pancreatitis, increased lipase 60 > 3x ULN and/or CRP values, radiological or intraoperative signs of acute pancreatitis)

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1 2

3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 - Chronic neuropathy > grade 2 5 - Renal failure, measured by GFR < 50 ml/min/1,73m2 (calculated according to CKD-EPI) 6 7 - Known liver cirrhosis of any grade 8 - Atrioventricular block 9 10 - Pregnant or breastfeeding women 11 - Mental or organic disorders, which could interfere with giving informed consent or receiving 12 treatments 13 14 - Any contraindication to propranolol and/or etodolac* 15 *for a list of all contraindications see supplemental appendix 16 17 18 Subject withdrawal For peer review only 19 20 Patients are free to leave the trial at any time and without giving reasons for their decision. Subjects may 21 be withdrawn from the trial for the following reasons: 22 23 a) at their own request, or 24 25 b) if, in the investigator’s opinion, continuation of the trial would be detrimental to the 26 subject’s well-being, e.g. symptomatic bradycardia after start of treatment, allergic reactions 27 28 to trial treatment, etc. In case of (b), the reason for withdrawal must be recorded in the case 29 report form (CRF) and in the patient’s medical records. 30 31 Patients, who withdrew or were withdrawn from the trial, will not be replaced. 32 33 34 Sample size 35 36 Since the current trial is conducted in an exploratory stage and not confirmatory, no formal sample size 37 calculation was performed. The sample size of 40 patients per group was judged to be sufficient for an http://bmjopen.bmj.com/ 38 39 assessment of safety and feasibility by a panel of clinical and methodological experts at the 40 investigators’ institution. All analyses will be interpreted as exploratory. Considering a dropout rate of 41 42 approximately 20%, a total of 100 patients will be randomized within the trial. The estimated patient 43 44 flow within the trial is depicted in figure 1. 45 on September 28, 2021 by guest. Protected copyright. 46 47 Trial procedures 48 Perioperative combination therapy 49 50 There will be one experimental arm (A) and one control arm (B): 51 52 A. Propranolol + etodolac 53 B. Placebo 54 55 ARM A: Oral intake of propranolol 2 x 20 mg/day for 10 days preoperatively, 2 x 40 mg for the day of 56 surgery and one week after surgery, 2 x 20 mg for the second postoperative week combined with oral 57 58 intake of etodolac 2 x 400 mg/day for a total of 25 days perioperatively (starting at 10 days 59 preoperatively). The dosage is summarized in table 1. 60 ARM B: Oral intake of placebo tablets/capsules of the same appearance, size, and weight as propranolol 6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 28

1 2 3 and etodolac. Placebo will be taken 2 x /day for a total of 25 days perioperatively (starting at 10 days BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 preoperatively). 6 7 8 Table 1: Dosage of trial medication 9 Time point Morning Evening 10 11 P 20 mg P 20 mg 10 Preop. Days 12 E 400 mg E 400 mg 13 P 40 mg P 40 mg 14 Day of surgery E 400 mg E 400 mg 15 16 P 40 mg P 40 mg POD 1 - 7 17 E 400 mg E 400 mg 18 For peer reviewP 20 mg Ponly 20 mg 19 POD 8 - 14 E 400 mg E 400 mg 20 21 P = propranolol or corresponding placebo; E = etodolac or corresponding placebo; POD: postoperative 22 day 23 24 25 With regard to current evidence and personal communications with experts on the combined 26 27 administration of propranolol and etodolac, we propose to use the dose of etodolac that was used by 28 29 Bhattacharyya et al. in their clinical trial in metastatic PDAC and in the perioperative trial in colorectal 30 cancer of Ben-Eliyahu and colleagues.20 21 Propranolol will be used in a standard dose of 2 x 20 mg, 31 32 which was also used by Ben-Eliyahu and colleagues in their colorectal cancer trial and an increased dose 33 of 2 x 40 mg on the day of surgery and the first postoperative week due to the increased stress factors 34 35 in this period.21

36 20 37 Bhattacharyya et al. observed no treatment-associated serious adverse events. Equally, in the http://bmjopen.bmj.com/ 38 perioperative colorectal cancer trial the combination therapy appeared safe with only one case of 39 40 symptomatic bradycardia that led to exclusion of the patient and two cases of tolerable bradycardia. 41 There were no differences in the rate of post-operative adverse events between the treatment and the 42 43 placebo groups.21 44 No dose adjustments are planned in individual subjects. In cases that require a temporary discontinuation 45 on September 28, 2021 by guest. Protected copyright. 46 of trial treatment (e.g. swallowing of tablets not possible due to severe gastroparesis; treatment on 47 48 intensive care unit with e.g. catecholamine therapy; etc.), the treatment will be paused and resumed as 49 soon as possible if reasonable. The percentage of the finally taken medication from the planned 50 51 medication will be documented in the CRF (adherence). 52 In case of any acute deterioration of health by any cause, the patients can and will be treated by any 53 54 appropriate measures without restrictions. 55 56 57 Surgery and biospecimen collection 58 59 Partial pancreatoduodenectomy will be performed according to local standards at the Department of 60 General, Visceral and Transplantation Surgery of the Heidelberg University Hospital.19 Postoperative

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1 2 3 care consists of a fast-track concept including a no-drain policy in routine cases, early mobilization and BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 early oral feeding. 6 For the translational part of the trial, peripheral blood samples will be collected during the screening 7 8 visit, the day before surgery, the day of surgery, on postoperative days (POD) 1, 3, 14 (or day of 9 discharge) and 3 months postoperatively. Additionally, portal venous blood will be taken 10 11 intraoperatively immediately after dissection of the hepatoduodenal ligament and before resection of the 12 3 13 tumor. Immediately after resection, a biopsy of 0.5-1cm will be excised from the resected 14 specimen for biobanking and molecular analysis in the translational part of the study. Detailed 15 16 methodology of the translational study will be described in a separate publication. 17 18 For peer review only 19 Trial endpoints 20 21 Safety endpoints 22 Safety will be evaluated by the rates of serious adverse events (SAE) and serious adverse reactions in 23 24 the two treatment groups within a period of three months postoperatively. 25 Further measurements of safety include postoperative mortality within 30 and 90 days, pancreas- 26 27 associated morbidity, such as postoperative pancreatic fistula (POPF) according to the up-dated ISGPS 28 (International Study Group of Pancreatic Surgery) definition,22 delayed gastric emptying and 29 30 postpancreatectomy hemorrhage according to the respective ISGPS definitions,23 24 postoperative biliary 31 25 32 leakage according to the ISGLS (International Study Group of Liver Surgery) definition and 33 postoperative intra-abdominal fluid collection or abscess. 34 35 36 Feasibility endpoints 37 http://bmjopen.bmj.com/ 38 Feasibility will be assessed by the evaluation of adherence to study medication intake. The rationale for 39 this endpoint is that there are some factors in the perioperative period, which might preclude patients 40 41 from taking the intended medication (e.g. delayed gastric emptying/gastroparesis, nausea/vomiting, 42 43 intolerable bradycardia under propranolol, etc.). This would hamper a wide-spread implementation into 44 treatment protocols. Adherence to study medication will thus provide more insight into the feasibility 45 on September 28, 2021 by guest. Protected copyright. 46 of implementing treatment with propranolol and etodolac into perioperative treatment plans. Adherence 47 to trial medication will be documented in a medication diary. Every patient will be asked to document 48 49 his drug intake or any impediments. Furthermore, all used or unused blister packs will need to be turned 50 51 in to the trial center by the patients. Opened packages with left-over investigational medicinal product 52 (IMPs) will be accounted for at the trial center. The percentage of the finally taken medication from the 53 54 planned medication will be documented in the electronic case report form (eCRF). 55 Furthermore, completion of adjuvant chemotherapy will be evaluated as another measure of feasibility. 56 57 This endpoint provides further insight into the practicality of implementing the trial intervention into 58 modern routine treatment schedules. 59 60

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1 2 3 Efficacy endpoints BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Overall and disease-free survival will be assessed as oncologic long-term variables. Survival is the 6 ultimate goal of any cancer directed therapy. Apart from overall survival, disease-free survival has been 7 8 proven to be a reliable parameter in phase II/III clinical trials. 9 Furthermore, rates of local and distant recurrence will be assessed as another efficacy outcome. 10 11 12 13 Biological endpoints 14 Biological endpoints/Biomarkers will be measured at different timepoints of study conduct as described 15 16 above. The following parameters will be assessed: 17 Blood samples: 18 For peer review only 19 1. Routine laboratory biomarkers: differential blood count, c-reactive protein (CRP), 20 albumin, carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) 21 22 2. Translational study biomarkers: phenotyping of circulating immune cells (FACS), 23 24 cytokine multiplex, PGE-2 levels, circulating tumor cells, RNA sequencing in periphery blood 25 cells (leukocytes) 26 27 Tissue samples (translational part of the study): 28 1. Biomarkers associated with COX-2 inhibition: COX-2, PGE-2, interleukin 6 (IL-6) 29 30 expression 31 32 2. Biomarkers associated with β-blockade: adrenoceptor beta 2 (ADRB2), vascular 33 endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2), matrix 34 35 metalloproteinase 4 (MMP4), S100, brain-derived neurotrophic factor (BDNF) expression 36 3. Characterization of the immune cell infiltrate (IHC) 37 http://bmjopen.bmj.com/ 38 4. RNA sequencing of bulk tissue or of sorted tumor and stromal cells 39 In addition, tumor cells will be cultures as organoids for further biological substudies. 40 41 42 43 Table 2 gives an overview of the clinical trial visits and displays which endpoints will be captured during 44 the respective visits. 45 on September 28, 2021 by guest. Protected copyright. 46 47 Table 2: Trial visits and assessment of endpoints 48 49 Visit Visit Visit Visit Visit Documentation Visit 2 Visit 3 Visit 8 Visit 9 50 1 4-6 7 10 11-13 51 52 53 54 55 POD 1/3/5 6/12/ POD 7 POD 30

56 3 months Screening 24 months

57 Day of surgery POD 14/ discharge Day before surgery 58 10-28daysafter V1 59 60 Eligibility criteria X X

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1 2 3 Baseline data, BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from X 4 demographics 5 Randomization X 6 Previous 7 X 8 medication Assessment 9 X X X X X X X 10 of safety Feasibility / 11 X X X X X X X adherence 12 Secondary 13 X X X X X endpoints* 14 Survival/ 15 X§ X§ X§ X§ X§ X§ X X recurrence 16 Routine blood 17 X X X X X sampling† 18 Blood sampling For peer review only 19 X X X X‡ X X translational tests 20 21 Tissue sampling X 22 * details of surgery, pathologic results (TNM stage), pancreas specific complications 23 † 24 blood count, CRP, creatinin, bilirubin, albumin, international normalized ratio (INR), CEA, CA 19-9 25 (Visit 1 and/or 2, 10), pregnancy test in case of childbearing potential (Visit 1) 26 27 ‡ POD 1 and 3 only 28 § only survival 29 30 31 32 Safety objectives and assessment of safety 33 All patients will be closely monitored for the occurrence of adverse events (AE). In this trial, all adverse 34 35 events will be documented from the first administration of the investigational medicinal products (10 36 days prior to surgery) until 3 months postoperatively. An AE is any untoward medical occurrence in a 37 http://bmjopen.bmj.com/ 38 trial subject administered an investigational medicinal product. There does not necessarily have to be a 39 causal relationship with the investigational medicinal product or any other trial-related procedure. A 40 41 serious adverse event (SAE) or serious adverse reaction (SAR) is any untoward medical occurrence, 42 43 without or with a reasonably possible causal relationship with the IMP, that at any dose: 44 1. results in death, 45 on September 28, 2021 by guest. Protected copyright. 46 2. is life-threatening at the time of the event, 47 3. requires inpatient hospitalization or prolongation of existing hospitalization, 48 49 4. results in persistent or significant disability/incapacity, 50 51 5. is a congenital anomaly or birth defect, 52 6. is, in the opinion of the investigator, otherwise medically relevant (e.g. requiring re- 53 54 laparotomy, endoscopic treatment or interventional percutaneous drainage, etc.). 55 Preexisting diseases are not documented as AE but as concomitant diseases. New diseases or 56 57 deteriorations of preexisting illnesses are also an AE in the context of this clinical trial. However, a 58 preexisting disease that leads to a treatment measure, which has already been planned before the start of 59 60 the clinical trial, is not regarded as an AE or SAE. Furthermore, changes of a preexisting disease, which

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1 2 3 represent the natural/expectable course of the disease are not regarded an AE. Routine medical treatment BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 after pancreatoduodenectomy will not be regarded as AE. In the postoperative period, expectable clinical 6 and/or laboratory findings (e.g. postoperative pain, delayed reuptake of bowel function, increase of CRP 7 8 and white blood cells, decrease of Hb-value, increase of liver function parameters, etc.) will not be 9 regarded as (S)AE as long as they are without deviation from the expectable clinical course. A list of 10 11 the expectable changes is included in the full trial protocol and can be obtained upon request from the 12 13 corresponding author. 14 The Data Safety Monitoring Board will receive listings of all SAE after the accrual of 20, 40 and 60 15 16 patients for review and assessment of patient risk and potential differences between the trial groups. 17 The Coordination Center for Clinical Trials (KKS) Heidelberg will be responsible for 18 For peer review only 19 pharmacovigilance and will provide a development safety update report once a year prepared according 20 to the International Council for Harmonisation (ICH) guideline E2F. 21 22 23 24 Ancillary translational study 25 In addition to routine blood sampling, which includes blood count, CRP, creatinine, bilirubin, albumin 26 27 and INR, blood samples for translational tests will be taken at the above-mentioned points of time. The 28 translational tests will consist of a cytokine multiplex (screening visit and day before surgery), PGE-2 29 30 levels (screening visit and day before surgery), circulating tumor cells (POD 3), RNA sequencing in 31 32 periphery blood cells (leukocytes; POD 3). The tumor tissue, which is sampled at surgery, will be 33 investigated by tissue cultures (organoids and pluripotent stem cells). Furthermore, COX-2 expression, 34 35 PGE-2 levels and immune cell infiltration will be investigated and RNA sequencing of bulk tissue or of 36 sorted tumor and stromal cells will be performed. 37 http://bmjopen.bmj.com/ 38 39 Data handling and monitoring 40 41 An investigator or a designated representative will enter all protocol-required data into the eCRF. All 42 43 entries in the eCRF must be verifiable by source documents. Data entries will undergo an automatic 44 online check for plausibility and consistency. Upon completion of the eCRF, the investigator has to 45 on September 28, 2021 by guest. Protected copyright. 46 confirm the accuracy of all data by signing sections online in the eCRF. 47 On site visits will be done by the monitor at regular intervals to ensure compliance with the trial protocol, 48 49 ICH good clinical practice (GCP) guidelines and legal aspects. The monitor must be given access to all 50 51 trial relevant documents by the investigator. He will review the entries into the eCRF for completeness 52 and correctness and verify the entries on the basis of the source documents. The responsible monitor 53 54 and the data manager can generate special questions (queries) that will be sent back to the responsible 55 investigator. The investigator or a designated representative will have to answer them all in a timely 56 57 manner. 58 Data management and monitoring activities will be performed according to the current standard 59 60 operating procedures of the Coordination Center for Clinical Trials (KKS) or the Study Center of the

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1 2 3 German Surgical Society (SDGC) respectively. BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 Statistical analysis 7 8 The main safety, efficacy and main feasibility variables will be analyzed with generalized linear models 9 or Cox regression models. Parameter estimates from these models will be reported with 95 percent 10 11 profile likelihood-based confidence intervals. All other variables will be tabulated by treatment group 12 using number of missing and non-missing values, the quartiles, mean and standard deviation. 13 14 All subjects who have ever been randomized to study treatment will form the full analysis set for efficacy 15 16 purposes. All patients will be analyzed according to the treatment group they have been randomized to, 17 regardless of the treatment they actually received (intention-to-treat). A restricted full analysis set will 18 For peer review only 19 be formed by the set of subjects undergoing surgical resection of the pancreas. Patients not undergoing 20 surgery at all or patients, who did not take at least 50% of their preoperative trial medication will be 21 22 replaced. The per-protocol set will comprise all patients receiving at least 75% per cent of study 23 24 medication at the appropriate time points. The safety set will contain all patients ever receiving study 25 medication and will assign patients to treatment group according to the treatment they actually received. 26 27 Analysis with respect to the main safety endpoints will be conducted using the safety set. Feasibility 28 will be compared using the full analysis set, whereas analysis on efficacy will be conducted using the 29 30 restricted full analysis set. A sensitivity analysis for efficacy will be per-formed for the per protocol set. 31 The rate of SAE/SAR will be used as the primary safety variable. It will be analyzed using a Poisson 32 33 regression model using the time under risk as an offset and treatment group as an explanatory variable. 34 35 36 Methods for minimizing bias 37 http://bmjopen.bmj.com/ 38 Minimizing selection bias: Patients will be consecutively screened and all eligible patients will be asked 39 for informed consent. All patients who have been screened but not included into the trial, will be 40 41 documented together with the respective reason for exclusion to assure transparency regarding patient 42 selection. Included patients will be allocated concealed by 1:1 randomization using a random list. Block 43 44 randomization of variable sizes will be performed. 45 on September 28, 2021 by guest. Protected copyright. 46 The pharmacy will manufacture consecutively numbered packages of trial medication of either verum 47 or placebo according to the random list and deliver these to the trial center on demand. On inclusion of 48 49 a new subject, the investigator or designated representative (e.g. a study nurse) will hand out the package 50 with the lowest remaining number to the patient and inform the monitoring about every new 51 52 randomization. 53 54 Minimizing performance and detection bias: Patients as well as all trial will be blinded with regard to 55 the trial drugs by means of placebo drugs in the control group. Since standard treatment is no specific 56 57 perioperative medication and no proven treatment during this period exists, which may improve 58 survival, the use of placebo is justified. Therefore, patients with placebo treatment will not be at risk of 59 60 harm.

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1 2 3 If it is medically imperative to know whether the patient receives verum or placebo, the investigator or BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 an authorized person should break the randomization code for the concerned patient. The investigator 6 or the person, who breaks the blind, must record the date and the reason for unblinding in the subject’s 7 8 medical record and in the randomization tool. Whenever possible, the principal investigator should be 9 contacted before the blind is broken. 10 11 Minimizing attrition and reporting bias: The trial will be reported according to the CONSORT 12 26 13 statement and to minimize reporting bias the trial was registered in advance in the German Clinical 14 Trials Registry DRKS (DRKS00014054), an approved Primary Register of the WHO International 15 16 Clinical Trials Registry Platform meeting the requirements of the International Committee of Medical 17 Journal Editors. For transparency regarding conduct and reporting of this trial, the protocol is hereby 18 For peer review only 19 published according to the SPIRIT statement.18 20 21 22 Ethics and regulatory aspects 23 24 Ethical basis for this trial are the principles described in the applicable version of the Declaration of 25 Helsinki.27 The present trial is conducted in accordance with the internationally recognized Good 26 27 Clinical Practice Guidelines (ICH-GCP), national regulatory requirements like the German Drug Law 28 (AMG) and German GCP Regulation, as well as the European regulations Directive 2001/20/EC and 29 30 Commission Directive 2005/28/EC. 31 32 Before start of the clinical trial, the trial was registered with EudraCT (2018-000415-25) and in the 33 German Clinical Trials Registry (DRKS00014054). The trial was approved by the competent authority, 34 35 the German Federal Institute for Drugs and Medical Devices (reference number 4042875 on August 28th 36 2018). Furthermore, the trial was reviewed by the Ethics Committee of the Medical Faculty of the 37 http://bmjopen.bmj.com/ 38 University of Heidelberg and was positively evaluated (reference number AFmo-385/2018 on August 39 10th 2018). 40 41 Data protection laws (Bundesdatenschutzgesetz and Landesdatenschutzgesetz Baden-Württemberg) as 42 43 well as the provisions of the General Data Protection Regulation (Regulation 2016/679 of the European 44 Union) will be respected. It is assured by the sponsor that all investigational materials and data will be 45 on September 28, 2021 by guest. Protected copyright. 46 pseudonymized in accordance with data protection legislation before scientific processing. 47 Trial drugs are licensed within the EU and dosage for each drug lies within the licensing 48 49 recommendations. For the combination propanolol/etodolac data have been published documenting 50 51 good tolerance. Exclusion criteria will guarantee that patients with preexisting severe diseases are 52 excluded. Therefore, the risk-benefit ratio for this selected patient group is positive. 53 54 Patients may not be enrolled into the present trial unless they have consented to take part in the trial 55 after having been informed verbally and in writing in comprehensible language of the nature, scope and 56 57 possible consequences by a trial investigator. Together with the consent to take part in the trial, the trial 58 subject must also agree to representatives of the sponsor (e.g. monitors or auditors) or the competent 59 60 supervisory or federal authorities having access to the data recorded within the framework of the clinical

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1 2 3 trial. The trial subject will be informed of the potential benefit and possible side effects of the IMP and BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 placebo, and of the need and rea-sons to conduct a placebo-controlled clinical trial. It must be clear to 6 trial subjects that he or she can withdraw his or her consent at any time without giving reasons and 7 8 without jeopardizing his / her further course of treatment. 9 10 11 Amendments to the trial protocol 12 13 Amendments made in accordance with § 10 Secs. 1 and 4 GCP Regulations that require approval are 14 submitted to the ethics committee and the federal higher authority and will not be implemented until 15 16 approved. 17 Since the start of the PROSPER trial, two amendments have been implemented and have been approved. 18 For peer review only 19 These included two relevant changes to the eligibility criteria: the exclusion criterion “Pre-operative CA 20 19-9 > 400 U/ml” was deleted during the first amendment and the exclusion criterion “Previous 21 22 neoadjuvant therapy” was deleted during the second amendment. This included the addition of a 23 24 subgroup analysis regarding efficacy of patients with vs. without neoadjuvant therapy. Furthermore, 25 details on neoadjuvant treatment (treatment protocol, dosage, etc.) will be documented together with the 26 27 baseline characteristics upon inclusion into the trial. Additionally, the amendments comprised only 28 minor changes and precisions, e.g. regarding the amount of blood sampled during the translational tests. 29 30 31 32 Patient and public involvement 33 Patients or the public were not directly involved in the development of this trial protocol. However, our 34 35 group conducted a priority setting partnership on pancreatic cancer identifying the most important 36 research questions by a priority setting group composed of patients, caregivers, members of patient 37 http://bmjopen.bmj.com/ 38 support groups and health-care professionals. The generated top ten list of research priorities included 39 several aspects that are addressed by this trial, e.g. “How can the best treatment for each individual 40 41 patient with PC be identified?”.28 Additionally, it is planned to distribute the results of this trial after its 42 43 completion within patient support groups such as the German “Arbeitskreis der Pankreatektomierten 44 e.V.”. 45 on September 28, 2021 by guest. Protected copyright. 46 47 Dissemination 48 49 It is planned to publish the trial results of this trial in a scientific, peer-reviewed journal and to present 50 51 the results at appropriate national or international scientific conferences. 52 Results from the accompanying translational part of the study will be published in mutual agreement 53 54 with the principal investigator of the clinical trial and the responsible investigator of the translational 55 study. 56 57 A full anonymized dataset of the trial results will be made available after trial completion and publication 58 upon reasonable request from the corresponding author. 59 60

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1 2 3 Author contributions BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 FJH, IR, GB, PK, JH, ALM, OS and MKD designed the study protocol. All authors contributed to the 6 study design. FJH, IR, GB, OS, MWB and MKD initiated this clinical study. FJH and MKD wrote the 7 8 paper. All authors approved the final version of this manuscript. All authors agreed to be accountable 9 for all aspects of the work, and ensure that any questions related to the accuracy or integrity of any 10 11 part of the work will be appropriately investigated and resolved. 12 13 14 15 16 Funding statement 17 This clinical trial is financed with donations of Het Anti-Kankerfonds (Anticancer Fund), a Belgian- 18 For peer review only 19 based private foundation. No commercial stakeholder was involved in the planning or conduct of this 20 trial. 21 22 23 24 25 Disclaimer 26 27 The funding source of the trial does not have a role in data collection, data analysis, or interpretation 28 of the trial results. 29 30 31 32 33 Competing interests statement 34 35 None declared. 36 37 http://bmjopen.bmj.com/ 38 39 Trial status 40 41 The first patient was included on January 11th 2019. Recruitment is currently ongoing. 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 Acknowledgements 47 We thank Inga Rossion (SDGC) and Liese Vandeborne (Anticancer Fund) for their ongoing support 48 49 regarding this trial in various aspects. Additionally, we appreciate the work of all contributors from the 50 51 Anticancer Fund, the KKS, the SDGC as well as from the clinical study center of the Department of the 52 General, Visceral and Transplantation Surgery of the University Heidelberg. Furthermore, we want to 53 54 acknowledge the honorary work of the members of the DSMB: Richard Jackson, Cancer Research UK 55 Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, United Kingdom; Paul Karanicolas 56 57 (Sunnybrooke Health Sciences Centre, Toronto, Ontario, Canada); Erica Sloan (Institute of 58 Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 59 60

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1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 1. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Lyon, France: 7 International Agency for Research on Cancer; 2018 [Available from: https://gco.iarc.fr/today 8 accessed 13-OCT-2019. 9 2. Arnold M, Rutherford M, Lam F, Bray F, Ervik M, Soerjomataram I. ICBP SURVMARK-2 online 10 tool: International Cancer Survival Benchmarking. Lyon, France.: International Agency for 11 Research on Cancer; 2019 [Available from: http://gco.iarc.fr/survival/survmark accessed 05 12 APR 2020. 13 14 3. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Tomorrow. Lyon, France.: 15 International Agency for Research on Cancer.; 2018 [Available from: 16 https://gco.iarc.fr/tomorrow accessed 05 April 2020. 17 4. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet 2016;388(10039):73-85. doi: 18 10.1016/S0140-6736(16)00141-0For peer [published review Online First: only 2016/02/03] 19 5. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for 20 Pancreatic Cancer. N Engl J Med 2018;379(25):2395-406. doi: 10.1056/NEJMoa1809775 21 [published Online First: 2018/12/24] 22 6. Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK. Perioperative events influence cancer 23 recurrence risk after surgery. Nat Rev Clin Oncol 2018;15(4):205-18. doi: 24 10.1038/nrclinonc.2017.194 [published Online First: 2017/12/29] 25 7. Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK. Sympathetic nervous system 26 regulation of the tumour microenvironment. Nat Rev Cancer 2015;15(9):563-72. doi: 27 10.1038/nrc3978 [published Online First: 2015/08/25] 28 8. Horowitz M, Neeman E, Sharon E, Ben-Eliyahu S. Exploiting the critical perioperative period to 29 improve long-term cancer outcomes. Nat Rev Clin Oncol 2015;12(4):213-26. doi: 30 10.1038/nrclinonc.2014.224 [published Online First: 2015/01/21] 31 9. Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer 2010;10(3):181-93. doi: 32 10.1038/nrc2809 [published Online First: 2010/02/20] 33 34 10. Mao Y, Sarhan D, Steven A, Seliger B, Kiessling R, Lundqvist A. Inhibition of tumor-derived 35 prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers 36 natural killer cell activity. Clin Cancer Res 2014;20(15):4096-106. doi: 10.1158/1078- 37 0432.CCR-14-0635 [published Online First: 2014/06/08] http://bmjopen.bmj.com/ 38 11. Zelenay S, van der Veen AG, Bottcher JP, et al. Cyclooxygenase-Dependent Tumor Growth 39 through Evasion of Immunity. Cell 2015;162(6):1257-70. doi: 10.1016/j.cell.2015.08.015 40 [published Online First: 2015/09/08] 41 12. Karnezis T, Shayan R, Caesar C, et al. VEGF-D promotes tumor metastasis by regulating 42 prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 43 2012;21(2):181-95. doi: 10.1016/j.ccr.2011.12.026 [published Online First: 2012/02/22] 44 13. Kumar P, Shen Q, Pivetti CD, Lee ES, Wu MH, Yuan SY. Molecular mechanisms of endothelial 45

hyperpermeability: implications in inflammation. Expert Rev Mol Med 2009;11:e19. doi: on September 28, 2021 by guest. Protected copyright. 46 10.1017/S1462399409001112 [published Online First: 2009/07/01] 47 14. Le CP, Nowell CJ, Kim-Fuchs C, et al. Chronic stress in mice remodels lymph vasculature to 48 promote tumour cell dissemination. Nat Commun 2016;7:10634. doi: 10.1038/ncomms10634 49 [published Online First: 2016/03/02] 50 15. Bertolini F, Sukhatme VP, Bouche G. Drug repurposing in oncology--patient and health systems 51 opportunities. Nat Rev Clin Oncol 2015;12(12):732-42. doi: 10.1038/nrclinonc.2015.169 52 53 [published Online First: 2015/10/21] 54 16. Pantziarka P, Verbaanderd C, Sukhatme V, et al. ReDO_DB: the repurposing drugs in oncology 55 database. Ecancermedicalscience 2018;12:886. doi: 10.3332/ecancer.2018.886 [published 56 Online First: 2019/01/27] 57 17. Ricon I, Hanalis-Miller T, Haldar R, Jacoby R, Ben-Eliyahu S. Perioperative biobehavioral 58 interventions to prevent cancer recurrence through combined inhibition of beta-adrenergic and 59 cyclooxygenase 2 signaling. Cancer 2019;125(1):45-56. doi: 10.1002/cncr.31594 [published 60 Online First: 2018/10/07]

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1 2 3 18. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 items for clinical trials. Ann Intern Med 2013;158(3):200-7. doi: 10.7326/0003-4819-158-3- 5 201302050-00583 [published Online First: 2013/01/09] 6 19. Schneider M, Strobel O, Hackert T, Buchler MW. Pancreatic resection for cancer-the Heidelberg 7 technique. Langenbecks Arch Surg 2019;404(8):1017-22. doi: 10.1007/s00423-019-01839-1 8 [published Online First: 2019/11/16] 9 20. Bhattacharyya GS, Babu KG, Bondarde SA, et al. Effect of coadministered beta blocker and COX- 10 2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) 11 12 paclitaxel. J Clin Oncol 2015;33 13 21. Zmora O, Shaashua L, Gutman M, Ben-Eliyahu S. The perioperative use of a beta-adrenergic 14 blocker and a COX-2 inhibitor in colorectal cancer patients for the prevention of cancer 15 recurrence: A preliminary study assessing feasibility and safety. Brain, Behavior, and 16 Immunity 2016;57 17 22. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group 18 (ISGPS) definitionFor and peergrading of postoperative review pancreatic only fistula: 11 Years After. Surgery 19 2017;161(3):584-91. doi: 10.1016/j.surg.2016.11.014 [published Online First: 2017/01/04] 20 23. Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a 21 suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 22 2007;142(5):761-8. doi: 10.1016/j.surg.2007.05.005 [published Online First: 2007/11/06] 23 24. Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage (PPH): an International Study 24 Group of Pancreatic Surgery (ISGPS) definition. Surgery 2007;142(1):20-5. doi: 25 10.1016/j.surg.2007.02.001 [published Online First: 2007/07/17] 26 25. Koch M, Garden OJ, Padbury R, et al. Bile leakage after hepatobiliary and pancreatic surgery: a 27 definition and grading of severity by the International Study Group of Liver Surgery. Surgery 28 2011;149(5):680-8. doi: 10.1016/j.surg.2010.12.002 [published Online First: 2011/02/15] 29 26. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for 30 31 reporting parallel group randomised trials. BMJ 2010;340:c332. doi: 10.1136/bmj.c332 32 [published Online First: 2010/03/25] 33 27. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles 34 for medical research involving human subjects. JAMA 2013;310(20):2191-4. doi: 35 10.1001/jama.2013.281053 [published Online First: 2013/10/22] 36 28. Klotz R, Dörr-Harim C, Ahmed A, et al. Top ten research priorities for the treatment of pancreatic 37 cancer. Lancet Oncol 2020;[accepted for publication] http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 FIGURE LEGENDS BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 Figure 1. Trial flowchart: OP = Operation, surgical intervention, POD = postoperative day, N, n = 7 8 number 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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BMJ Open Page 20 of 28 Assessed for eligibility 1 n = 480 2 Patients with resectable carcinoma of the pancreatic head 3 planned for pancreatoduodenectomy 4 5 Excluded n = 380 6 - Not meeting eligibility criteria 7 Enrolment - Declined to participate 8 - Other reasons 9 10 Visit 1 11 Eligible patients with written informed consent 12 13 For peerTo be randomized review n = 100 only 14 15 16 17 18 Treatment group Placebo control group Excluded 19 (Propranolol + etodolac) N = 10 20 (no intake of 21 n = 50 n = 50 trial drugs, no 22 Allocation 23 operation) 24 Visit 2 OP Day - 1 OP Day - 1 25 26

27 http://bmjopen.bmj.com/ Visit 3 OP Day OP Day 28 29 30 31 Visit 4 - 6 POD 1/ 3/ 5 POD 1/ 3/ 5 32 33 34 Visit 7 POD 7 POD 7

35 on September 28, 2021 by guest. Protected copyright. 36 Excluded 37 up Visit 8 POD 14/ discharge POD 14/ discharge 38 - N = 10 39 (Drop-outs, 40 losses to 41 Follow Visit 9 POD 30 POD 30 follow-up) 42 43 44 Visit 10 3 months 3 months 45 46 47 Visit 11-13 6/ 12/ 24 months 6/ 12/ 24 months 48 49 50 51 52 To be analyzed To be analyzed 53 n = 40 n = 40

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1 2 3 Appendix 1: List of contraindications to propranolol and/or etodolac: BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5  Known allergy or hypersensitivity to propranolol and/or etodolac and/or any other ingredient of the 6 used brands 7  History or evidence of significant cardiac disease: congestive or severe heart failure; New York Heart 8 Association class ≥ 2; active coronary artery disease; unstable angina, cardiac arrhythmias requiring 9 anti-arrhythmic therapy, uncontrolled hypertension, patients with recent (less than 6 months) 10 myocardial infarction or coronary re-vascularization; cardiogenic shock; sick sinus syndrome; sinoatrial 11 block; acidosis 12  Hypotension at the time of screening (i.e., systolic blood pressure < 100 mmHg. Diastolic blood 13 pressure < 60 mmHg) 14  Symptomatic bradycardia or resting heart rate < 50 bpm at time of screening 15  Bronchial hyperresponsiveness, including active chronic asthma 16  Active peptic ulcer disease or gastrointestinal bleeding 17  Decompensated diabetes mellitus (repeated measurements of glucose > 300 mg/dl despite usual medical 18 treatment, (keto-)For acidosis, peer exsiccosis due review to decompensated diabetes)only 19  Chronic inflammatory bowel disease (M. Crohn or Ulcerative colitis) 20  Severe peripheral vascular disease 21  Concurrent use of monoaminooxidase inhibitor (excluding monoaminooxidase-B inhibitor) 22  Intravenous application of calcium channel blockers (non-dihydropyridine) and other antiarrhythmic 23 agents 24  Severe thrombocytopenia 25  Sensitivity to aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) in terms of asthma, 26 urticarial or acute rhinitis 27  Chronic use of any beta-adrenergic blocker within the last 3 months 28  Chronic use of any cyclooxygenase (COX) inhibitor within the last 3 months 29  Participation in another interventional trial 30  Pharmaceutical preparations with which major interactions can be expected by propranolol and/or 31 etodolac in patients’ long-term therapy* 32  Diseases or findings that may have a significant effect on the target variables and which may therefore 33 mask or inhibit the therapeutic effect under investigation 34  Persons with any kind of dependency on the investigator or employed by the sponsor or investigator 35  Persons held in an institution by legal or official order; legally incapacitated patients 36  Persons with understanding/language problems or inability to comply with study and/or follow-up 37 procedures http://bmjopen.bmj.com/ 38  Any condition which could result in an undue risk for the patient and/or influence out-come measures in 39 the opinion of the investigator 40 41 *see Appendix 2 for possible interactions 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Appendix 2: Possible major interactions with patient’s concomitant medication BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 A) Etodolac: 6 Severity: Major 7 Risk rating: Avoid combination 8  NSAIDs and selective COX-2 inhibitors may enhance the adverse/toxic effect of Etodolac. 9  Etodolac (as a photosensitizing agent) may enhance the photosensitizing effect of Aminolevulinic Acid 10 (5-ALA). Avoid administration of other photosensitizing agents within 24 hours before or 24 hours 11 after orally administered 5-ALA. As 5-ALA is administered for visualization of malignant tissue in 12 glioma patient, it is unlikely that study participant experience this kind of interaction. 13  Etodolac may enhance the anticoagulant effect of Urokinase. 14 15 Severity: Major 16 Risk rating: Consider therapy modification 17  Etodolac may enhance the adverse/toxic effect of Apixaban, Rivaroxaban, Dabigatran Etexilate, 18 Edoxaban. Specifically,For thepeer risk of bleeding review may be increased. only If combined, monitor patients extra 19 closely for signs and symptoms of bleeding with any concurrent use, and counsel patients about the 20 increased risk of bleeding and the need to promptly report any signs or symptoms of possible bleeding. 21  Monitor for decreased serum concentrations/therapeutic effects Etodolac if coadministered with bile 22 acid sequestrants (Cholestyramine Resin). Separating the administration of doses by 2 or more hours may reduce (but not eliminate) the risk of interaction. 23  Etodolac may enhance the nephrotoxic effect of Cyclosporine. Monitor for evidence of nephrotoxicity, 24 as well as increased serum cyclosporine concentrations and systemic effects (e.g. hypertension) during 25 concomitant therapy. 26  Etodolac may increase the serum concentration of Lithium. Consider reducing the dosage of lithium 27 upon initiation of Etodolac. Monitor for increased therapeutic/toxic effects of lithium if Etodolac is 28 initiated/dose increased, or decreased effects if Etodolac is discontinued/dose decreased. 29  Etodolac may increase the serum concentration of Methotrexate. If methotrexate and Etodolac are to be 30 used concomitantly, monitor patients for evidence of hematologic toxicity (frequent complete blood 31 count), nephrotoxicity (frequent serum creatinine), and hepatotoxicity (liver function tests). 32  Etodolac may enhance the adverse/toxic effect of Salicylates (excluding low dose acetyl-salicylic acid, 33 e.g. aspirin 100 mg/day). 34  Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Etodolac. Etodolac may 35 diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. To minimize the risk of 36 bleeding associated with this combination, consider using alternative analgesics, when appropriate, 37 and/or addition of a gastroprotective agent, such as a proton pump inhibitor for the time that combined http://bmjopen.bmj.com/ 38 therapy is necessary. 39  Sodium Phosphates may enhance the nephrotoxic effect of Etodolac. Specifically, the risk of acute 40 phosphate nephropathy may be enhanced. This interaction has only been demonstrated with large oral 41 sodium phosphate doses used for bowel preparation (typically greater than 20 g). 42  Etodolac may enhance the nephrotoxic effect of Tenofovir Products. Avoid concurrent use of tenofovir 43 with high-dose of Etodolac when possible due to a potential risk for acute renal failure. This risk has 44 been most clearly shown with the NSAID diclofenac, but some data suggest that other NSAIDs may 45 also be capable of interacting with tenofovir. on September 28, 2021 by guest. Protected copyright. 46  Etodolac may enhance the anticoagulant effect of Vitamin K Antagonists (Acenocoumarol, 47 Phenindione, Warfarin). Monitor for increased signs and symptoms of bleeding. 48 49 B) Propranolol: 50 Severity: Major 51 Risk rating: Avoid combination 52  Propranolol may diminish the bronchodilatory effect of Beta-2-Agonists (Bambuterol, Fenoterol, 53 Formoterol, Indacaterol, Levosalbutamol, Olodaterol, Orciprenalin, Salbutamol, Salmeterol, 54 Terbutaline, Vilanterol). 55  Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Avoid concurrent use of 56 ceritinib with propranolol when possible. If such use cannot be avoided, monitor patients for evidence 57 of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. 58 Adjustment of ceritinib therapy (i.e., dose reduction and/or temporary discontinuation) may be 59 necessary for symptomatic bradycardia. 60  Propranolol may enhance the adverse/toxic effect of Methacholine. Methacholine administration is contraindicated in patients receiving any beta-blocker.

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1 2 3  Rivastigmine may enhance the bradycardic effect of propranolol. Due to the risk of additive BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 bradycardic effects, including syncope, the concomitant use of rivastigmine and beta-blockers is not 5 recommended. 6 7 Severity: Major 8 Risk rating: Consider therapy modification 9  Abiraterone Acetate may increase the serum concentration of propranolol (as a CYP2D6 substrate). 10 When concurrent use is not avoidable, monitor patients closely for signs/symptoms of propranolol 11 toxicity. 12  CYP2D6 inhibitors: Fluoxetine, Paroxetine, Quinidine, Tipranavir may decrease the metabolism of 13 propranolol. Consider an alternative for one of the interacting drugs in order to avoid toxicity of 14 propranolol. Some combinations are specifically contraindicated by manufacturers. Suggested dosage 15 adjustments are also offered by some manufacturers. Please review applicable package inserts. Monitor 16 for increased effects of propranolol if a cytochrome P (CYP) inhibitor is initiated/dose increased, and 17 decreased effects if a CYP inhibitor is discontinued/dose decreased. 18  Dronedarone mayFor enhance peer the bradycardic review effect of propranolol only and increase the serum concentration 19 of propranolol. 20  Fluvoxamine (as a CYP1A2 inhibitor) may increase effects of propranolol is initiated/dose increased, 21 and decrease effects if fluvoxamine is discontinued/dose decreased. 22  Propranolol may enhance the vasopressor effect of direct-acting Alpha-/Beta-Agonists (Dopamine, 23 Ephedrine (Nasal), Ephedrine (Systemic), Epinephrine (Nasal), Epinephrine (Oral Inhalation), Epinephrine (Systemic), Isometheptene, Levonordefrin, Metaraminol, Norepinephrine). Epinephrine 24 used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some 25 beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti- 26 anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Monitor for increases in 27 pressor effects of alpha-/beta-agonists if used in patients receiving propranolol. Beta-1-selective (i.e., 28 “cardioselective”) agents may confer a more limited risk if used in low enough doses to allow them to 29 retain their selectivity. Infiltrating larger volumes of local anesthetics for other surgical procedures 30 (e.g., more than 0.06mg epinephrine) may cause clinically-relevant problems. Patients with allergies 31 that require carrying and periodically using subcutaneous epinephrine (e.g. bee sting kits) should 32 probably avoid the use of propranolol. 33  Alpha-2-Agonists (Brimonidine (Ophthalmic), Clonidine, Dexmedetomidine, Guanfacine, Lofexidine, 34 Methyldopa, Moxonidine, Rilmenidine, Tizanidine, Excep-tion: Apraclonidine) may enhance the atrio- 35 ventricular-blocking (AV-block) effect of propranolol. Sinus node dysfunction may also be enhanced. 36 Propranolol may enhance the re-bound hypertensive effect of Alpha-2-Agonists. This effect can occur 37 when the Alpha-2-Agonist is abruptly withdrawn. http://bmjopen.bmj.com/ 38  Propranolol may enhance the hypotensive effect of Amifostine. Amifostine should not be administered 39 when propranolol is concomitantly used. 40  Propranolol may enhance the vasoconstricting effect of Ergot Derivatives (Bromocriptine, Cabergoline, 41 Dihydroergotamine, Ergoloid Mesylates, Ergonovine, Ergotamine, Methylergonovine, Pergolide, 42 Exception: Nicergoline). Consider alternatives whenever possible in order to avoid this combination. If 43 concurrent use cannot be avoided, monitor patients closely for evidence of excessive peripheral 44 vasoconstriction. 45  Beta-Blockers may enhance the bradycardic effect of Fingolimod. Avoid the concomitant use of on September 28, 2021 by guest. Protected copyright. 46 fingolimod and beta-blockers if possible. If co-administration is necessary, patients should have 47 overnight continuous electrocardiogram monitoring conducted after the first dose of fingolimod. 48 Closely monitor patients for the development of bradycardia and other serious arrhythmias. 49  Obinutuzumab may enhance the hypotensive effect of propranolol. In order to minimize the risk of 50 excessive hypotension during or immediately after obinutuzumab infusion, clinicians should consider 51 temporarily withholding propranolol beginning 12 hours prior to infusion and continuing until 1 hour 52 after infusion and until the patient's blood pressure is stable. 53  Panobinostat may increase the serum concentration of propranolol. Avoid concurrent use of propranolol 54 when possible. If such a combination cannot be avoided, monitor patients closely for evidence of 55 propranolol toxicity. 56  Propranolol may increase the serum concentration of Rizatriptan. Rizatriptan dose should be reduced to 5mg in patients who are also being treated with propranolol. Monitor clinical response to rizatriptan 57 closely with use of this combination. 58  Propranolol may diminish the bronchodilatory effect of Theophylline Derivatives (Acebrophylline, 59 Aminophylline, Dyphylline, Theophylline). Consider avoiding the concomitant use of propranolol and 60 theophylline derivatives. If concomitant use cannot be avoided, monitor for symptoms of reduced theophylline efficacy.

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1 2 3  Propranolol may increase the serum concentration of Tizanidine. Avoid the use of tizanidine with BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 propranolol when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 5 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of 6 tizanidine, including adverse reactions (e.g. hypotension, bradycardia, drowsiness). 7  Vemurafenib may increase the serum concentration of propranolol. Consider alternatives to such 8 combinations whenever possible. 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 7 8 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and 9 related documents* 10 11 Section/item Item Description 12 No 13 14 Administrative information 15 16 Title 1 Descriptive title identifying the study design, population, interventions, 17 and, if applicable, trial acronym ➔ Pg. 1 18 For peer review only 19 Trial registration 2a Trial identifier and registry name. If not yet registered, name of 20 intended registry ➔ Pg. 2 21 22 2b All items from the World Health Organization Trial Registration Data 23 24 Set ➔ Pg. 2 25 26 Protocol version 3 Date and version identifier ➔ Pg. 2 27 28 Funding 4 Sources and types of financial, material, and other support ➔ Pg. 17 29 Roles and 5a Names, affiliations, and roles of protocol contributors 30 ➔ Pg. 1 & 17 31 responsibilities 5b Name and contact information for the trial sponsor ➔ Pg. 1 32 33 5c Role of study sponsor and funders, if any, in study design; collection, 34 35 management, analysis, and interpretation of data; writing of the report; 36 and the decision to submit the report for publication, including whether 37 they will have ultimate authority over any of these activities ➔ Pg. 17 http://bmjopen.bmj.com/ 38 39 5d Composition, roles, and responsibilities of the coordinating centre, 40 steering committee, endpoint adjudication committee, data 41 42 management team, and other individuals or groups overseeing the 43 trial, if applicable (see Item 21a for data monitoring committee) ➔ Pg. 44 17 45 on September 28, 2021 by guest. Protected copyright. 46 Introduction 47 48 Background and 6a Description of research question and justification for undertaking the 49 50 rationale trial, including summary of relevant studies (published and 51 unpublished) examining benefits and harms for each intervention ➔ 52 Pg. 3-4 53 54 6b Explanation for choice of comparators ➔ Pg. 7 55 56 Objectives 7 Specific objectives or hypotheses ➔ Pg. 4 57 58 59 60

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1 2 Trial design 8 Description of trial design including type of trial (eg, parallel group, 3 crossover, factorial, single group), allocation ratio, and framework (eg, BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 superiority, equivalence, noninferiority, exploratory) ➔ Pg. 4 5 6 7 8 Methods: Participants, interventions, and outcomes 9 10 Study setting 9 Description of study settings (eg, community clinic, academic hospital) 11 and list of countries where data will be collected. Reference to where 12 list of study sites can be obtained ➔ Pg. 4 13 14 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility 15 16 criteria for study centres and individuals who will perform the 17 interventions (eg, surgeons, psychotherapists) ➔ Pg. 5-6 18 For peer review only 19 Interventions 11a Interventions for each group with sufficient detail to allow replication, 20 including how and when they will be administered ➔ Pg. 7-8 21 22 11b Criteria for discontinuing or modifying allocated interventions for a 23 given trial participant (eg, drug dose change in response to harms, 24 25 participant request, or improving/worsening disease) ➔ Pg. 8 26 27 11c Strategies to improve adherence to intervention protocols, and any 28 procedures for monitoring adherence (eg, drug tablet return, 29 laboratory tests) ➔ Pg. 9 30 31 11d Relevant concomitant care and interventions that are permitted or 32 prohibited during the trial ➔ Pg. 11 33 34 Outcomes 12 Primary, secondary, and other outcomes, including the specific 35 measurement variable (eg, systolic blood pressure), analysis metric 36 37 (eg, change from baseline, final value, time to event), method of http://bmjopen.bmj.com/ 38 aggregation (eg, median, proportion), and time point for each 39 outcome. Explanation of the clinical relevance of chosen efficacy and 40 harm outcomes is strongly recommended ➔ Pg. 8-10 41 42 Participant 13 Time schedule of enrolment, interventions (including any run-ins and 43 44 timeline washouts), assessments, and visits for participants. A schematic 45 diagram is highly recommended (see Figure) ➔ Pg. 10-11 (Table 2) on September 28, 2021 by guest. Protected copyright. 46 47 Sample size 14 Estimated number of participants needed to achieve study objectives 48 and how it was determined, including clinical and statistical 49 assumptions supporting any sample size calculations ➔ Pg. 6-7 50 51 Recruitment 15 Strategies for achieving adequate participant enrolment to reach 52 53 target sample size ➔ Pg. 5 54 55 Methods: Assignment of interventions (for controlled trials) 56 Allocation: 57 58 59 60

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1 2 Sequence 16a Method of generating the allocation sequence (eg, computer- 3 generation generated random numbers), and list of any factors for stratification. BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 To reduce predictability of a random sequence, details of any planned 5 6 restriction (eg, blocking) should be provided in a separate document 7 that is unavailable to those who enrol participants or assign 8 interventions ➔ Pg. 13 9 10 Allocation 16b Mechanism of implementing the allocation sequence (eg, central 11 concealment telephone; sequentially numbered, opaque, sealed envelopes), 12 13 mechanism describing any steps to conceal the sequence until interventions are 14 assigned ➔ Pg. 13 15 16 Implementation 16c Who will generate the allocation sequence, who will enrol participants, 17 and who will assign participants to interventions ➔ Pg. 13 18 For peer review only 19 Blinding 17a Who will be blinded after assignment to interventions (eg, trial 20 (masking) participants, care providers, outcome assessors, data analysts), and 21 how ➔ Pg. 13-14 22 23 17b If blinded, circumstances under which unblinding is permissible, and 24 25 procedure for revealing a participant’s allocated intervention during 26 the trial ➔ Pg. 14 27 28 Methods: Data collection, management, and analysis 29 30 Data collection 18a Plans for assessment and collection of outcome, baseline, and other 31 methods trial data, including any related processes to promote data quality (eg, 32 duplicate measurements, training of assessors) and a description of 33 34 study instruments (eg, questionnaires, laboratory tests) along with 35 their reliability and validity, if known. Reference to where data 36 collection forms can be found, if not in the protocol ➔ Pg. 8-12 37 http://bmjopen.bmj.com/ 38 18b Plans to promote participant retention and complete follow-up, 39 including list of any outcome data to be collected for participants who 40 41 discontinue or deviate from intervention protocols ➔ Pg. 12 42 Data 19 Plans for data entry, coding, security, and storage, including any 43 44 management related processes to promote data quality (eg, double data entry; 45 range checks for data values). Reference to where details of data on September 28, 2021 by guest. Protected copyright. 46 management procedures can be found, if not in the protocol ➔ Pg. 12 47 48 Statistical 20a Statistical methods for analysing primary and secondary outcomes. 49 methods Reference to where other details of the statistical analysis plan can be 50 51 found, if not in the protocol ➔ Pg. 13 52 53 20b Methods for any additional analyses (eg, subgroup and adjusted 54 analyses) ➔ Pg. 13 55 56 20c Definition of analysis population relating to protocol non-adherence 57 (eg, as randomised analysis), and any statistical methods to handle 58 missing data (eg, multiple imputation) ➔ Pg. 13 59 60

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1 2 Methods: Monitoring 3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role 5 and reporting structure; statement of whether it is independent from 6 the sponsor and competing interests; and reference to where further 7 8 details about its charter can be found, if not in the protocol. 9 Alternatively, an explanation of why a DMC is not needed ➔ Pg. 12 & 10 17 11 12 21b Description of any interim analyses and stopping guidelines, including 13 who will have access to these interim results and make the final 14 decision to terminate the trial 15 ➔ 12 16 Harms 22 Plans for collecting, assessing, reporting, and managing solicited and 17 18 Forspontaneously peer review reported adverse only events and other unintended effects 19 of trial interventions or trial conduct ➔ Pg. 11-12 20 21 Auditing 23 Frequency and procedures for auditing trial conduct, if any, and 22 whether the process will be independent from investigators and the 23 sponsor ➔ n.a. 24 25 26 Ethics and dissemination 27 28 Research ethics 24 Plans for seeking research ethics committee/institutional review board 29 approval (REC/IRB) approval ➔ Pg. 14-15 30 31 Protocol 25 Plans for communicating important protocol modifications (eg, 32 amendments changes to eligibility criteria, outcomes, analyses) to relevant parties 33 (eg, investigators, REC/IRBs, trial participants, trial registries, journals, 34 35 regulators) ➔ 15 36 37 Consent or assent 26a Who will obtain informed consent or assent from potential trial http://bmjopen.bmj.com/ 38 participants or authorised surrogates, and how (see Item 32) ➔ Pg. 15 39 40 26b Additional consent provisions for collection and use of participant data 41 and biological specimens in ancillary studies, if applicable ➔ n.a. 42 43 Confidentiality 27 How personal information about potential and enrolled participants will 44 be collected, shared, and maintained in order to protect confidentiality 45 before, during, and after the trial ➔ Pg. 14-15 on September 28, 2021 by guest. Protected copyright. 46 47 Declaration of 28 Financial and other competing interests for principal investigators for 48 49 interests the overall trial and each study site ➔ Pg. 17 50 51 Access to data 29 Statement of who will have access to the final trial dataset, and 52 disclosure of contractual agreements that limit such access for 53 investigators ➔ Pg. 15 54 55 Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and for 56 post-trial care compensation to those who suffer harm from trial participation ➔ 8 57 58 59 60

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1 2 Dissemination 31a Plans for investigators and sponsor to communicate trial results to 3 policy participants, healthcare professionals, the public, and other relevant BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 groups (eg, via publication, reporting in results databases, or other 5 6 data sharing arrangements), including any publication restrictions ➔ 7 Pg. 16 8 9 31b Authorship eligibility guidelines and any intended use of professional 10 writers ➔ Pg. 17 11 12 31c Plans, if any, for granting public access to the full protocol, participant- 13 level dataset, and statistical code ➔ Pg. 16 14 15 16 Appendices 17 Informed consent 32 Model consent form and other related documentation given to 18 For peer review only 19 materials participants and authorised surrogates ➔ upon request 20 21 Biological 33 Plans for collection, laboratory evaluation, and storage of biological 22 specimens specimens for genetic or molecular analysis in the current trial and for 23 future use in ancillary studies, if applicable ➔ 9-10, 12 24 25 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 26 Explanation & Elaboration for important clarification on the items. Amendments to the 27 protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT 28 29 Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” 30 license. 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Article Type: Protocol

Date Submitted by the 27-Jul-2020 Author:

Complete List of Authors: Hüttner, Felix; University of Heidelberg, Department of General, Visceral and Transplantation Surgery; University of Heidelberg, The Study Center of the German Surgical Society (SDGC) Rooman, Ilse; The Anticancer Fund; Vrije Universiteit Brussel, Laboratory of Medical and Molecular Oncology Bouche, Gauthier; The Anticancer Fund Knebel, Phillip; UniversitatsKlinikum Heidelberg, Department of General, Visceral and Transplantation Surgery Hüsing, Johannes; Heidelberg University, Coordination Center for Clinical Trials Mihaljevic, A; UniversitätsKlinikum Heidelberg, Thilo, Hackert; Heidelberg University, Department of General, Visceral and Transplantation Surgery http://bmjopen.bmj.com/ Strobel, Oliver ; Heidelberg University, Department of General, Visceral and Transplantation Surgery Buchler, Markus W.; UniversitätsKlinikum Heidelberg, Department of General, Visceral and Transplantation Surgery Diener, M. K.; Heidelberg University, Department of General, Visceral and Transplantation Surgery

Primary Subject Oncology Heading: on September 28, 2021 by guest. Protected copyright. Secondary Subject Heading: Surgery

Gastrointestinal tumours < ONCOLOGY, Adult oncology < ONCOLOGY, Keywords: Pancreatic surgery < SURGERY

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1 2 3 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Introduction 6 Pancreatic cancer is the fourth leading cause of cancer-related death in developed countries. Despite 7 8 advances in systemic chemotherapy, the mainstay of curative therapy for non-metastatic disease is 9 surgical resection. However, the perioperative period is characterized by stress and inflammatory 10 11 reactions that can contribute to metastatic spread and disease recurrence. Catecholamines and 12 13 prostaglandins play a crucial role in these reactions. Therefore, a drug repurposing of betablockers and 14 cyclooxygenase inhibitors seems reasonable to attenuate tumor-associated inflammation by inhibiting 15 16 psychological, surgical and inflammatory stress responses. This may cause a relevant antitumorigenic 17 and antimetastatic effect during the perioperative period, a window for cancer-directed therapy that is 18 For peer review only 19 currently largely unexploited. 20 21 22 Methods and analysis 23 24 This is a prospective, single-center, two-arm randomized, patient and observer blinded, placebo- 25 controlled, phase-2 trial evaluating safety and feasibility of combined perioperative treatment with 26 27 propranolol and etodolac in adult patients with non-metastatic cancer of the pancreatic head undergoing 28 elective pancreatoduodenectomy. 100 patients fulfilling the eligibility criteria will be randomized to 29 30 perioperative treatment for 25 days perioperatively with a combination of propranolol and etodolac or 31 32 placebo. Main outcome of interest will be safety in terms of serious adverse events and reactions within 33 3 months. Furthermore, adherence to trial medication will be assessed as feasibility outcomes. 34 35 Preliminary efficacy data in terms of survival and tumor recurrence within 2 years will also be evaluated. 36 The clinical trial is accompanied by a translational study investigating the mechanisms of action of the 37 http://bmjopen.bmj.com/ 38 combined therapy on a molecular basis. 39 40 41 Ethics and dissemination 42 43 The PROSPER-trial has been approved by the German Federal Institute for Drugs and Medical Devices 44 (reference number 4042875) and the Ethics Committee of the Medical Faculty of the University of 45 on September 28, 2021 by guest. Protected copyright. 46 Heidelberg (reference number AFmo-385/2018). The final trial results will be published in a peer 47 reviewed journal and will be presented at appropriate national and international conferences. 48 49 50 51 Trial registration number 52 DRKS00014054; EudraCT number: 2018-000415-25 53 54 55 56 57 58 59 60

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1 2 3 Strengths and limitations of this study BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 - This is the first clinical trial assessing a combined treatment with a betablocker (propranolol) 6 and a cyclooxygenase inhibitor (etodolac) in the perioperative period surrounding partial 7 8 pancreatoduodenectomy for cancer of the pancreatic head. 9 10 - Strengths of this study are its randomized, double-blind, placebo-controlled design and its 11 transparent design with the clear definitions of endpoints. 12 13 - Potential limitation include the rather small sample size leading to a limited power and the 14 broad exclusion criteria, which may limit generalizability of the data, because of the selected 15 16 trial population. 17 - If the trial treatment proves to be safe, the perioperative period may be used as a window for 18 For peer review only 19 cancer-directed therapy and the results will form the basis for a subsequent phase III trial. 20 21 22 INTRODUCTION 23 24 More than 450,000 new cases of pancreatic cancer are diagnosed worldwide per year.1 In contrast to 25 many other cancers, its incidence and mortality have been rising during the last decades and the 26 27 prognosis is devastating with a 5-year overall survival of < 10%.2 3 Despite substantial advancements in 28 29 systemic chemotherapy during recent years, the mainstay of curatively intended treatment remains 30 surgical resection. However, only a small proportion of patients present with potentially resectable 31 4 32 disease (primary resectable or borderline resectable) at diagnosis. With modern multimodal treatment 33 strategies consisting of resection and adjuvant chemotherapy, a median overall survival of 54 months 34 35 can be reached, but disease-free survival at three years is still < 50% in these patients.5 36 For patients with potentially resectable tumors, the perioperative time period, which spans an 37 http://bmjopen.bmj.com/ 38 interval from the timepoint of diagnosis until the actual start of adjuvant chemotherapy, 39 6 40 represents a window of opportunity for perioperative therapy aimed to reduce recurrence. The 41 psychological stress and the emotions around diagnosis, surgery and upcoming chemotherapy 42 43 are accompanied by increased release of catecholamines exerting their effects on tumor cells 44 and stromal cells that express adrenergic receptors. On one hand, catecholamine release is 45 on September 28, 2021 by guest. Protected copyright. 46 an adaptive reaction to cope with stressful situations by modulating the immune response and 47 48 mobilizing metabolic reserves. On the other hand, these stress responses are also pro- 49 tumorigenic with pleiotropic effects on the primary tumor, the tumor microenvironment, 50 7 51 malignant cells in the circulation and on pre-existing micrometastases. Interestingly, the 52 effects of catecholamines may be counteracted by adrenergic receptor antagonists (beta- 53 54 blockers), often prescribed for hypertension or cardiac disease. 55 Surgically induced inflammation and the subsequent release of prostaglandins are additional 56 57 mediators of tumorigenic and pro-metastatic effects in the perioperative period despite their 58 8 59 role in tissue repair and regeneration. Prostaglandins facilitate tumor cell survival, proliferation 60 and invasion and also counteract immunosurveillance.9-11 Prostaglandins promote

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1 2 3 angiogenesis and epithelial-mesenchymal transition and they lead to a release of pro-survival BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 7 8 5 and growth factors for malignant cells. In addition, prostaglandins promote microvascular 6 barrier dysfunction, endothelial hyperpermeability and lymphatic dilation, which can facilitate 7 8 lymphatic and distant metastases.12-14 Prostaglandin synthesis from arachidonic acid involves 9 the cyclooxygenases (COX), of which COX-2 is the inducible form that is particularly active 10 11 during inflammation by generating prostaglandin E2 (PGE-2). COX are druggable targets and 12 13 the above-mentioned effects could be counteracted by selective COX-2 inhibitors. 14 The term ‘drug repurposing’ describes an approach trying to repurpose well-characterised drugs for a 15 16 previously untested indication. This emerging strategy is of particular interest for oncologic purposes.15 17 16 In terms of drug repurposing a combination therapy of propranolol, a non-selective beta-blocker, and 18 For peer review only 19 etodolac, a semiselective COX-2 inhibitor, in the perioperative setting of pancreatic cancer resection 20 may result in attenuation of tumor-associated inflammation and stress responses..17 By these 21 22 mechanisms, it may cause a relevant antitumorigenic and antimetastatic effect during the perioperative 23 24 period, which is a currently largely unexploited window for therapies aiming to influence these stress 25 and inflammatory responses. Promising results of this ‘drug repurposing’ have been shown in both, 26 27 preclinical and early clinical trials for other solid cancer entities. In an experimental liver metastasis 28 mouse model of colorectal cancer, treatment with propranolol and etodolac reduced hepatic metastases 29 30 in the context of surgery.18 Furthermore, in a phase-2 randomized controlled trial on colorectal cancer, 31 32 the treatment was well tolerated and showed favorable results regarding early biomarkers of metastatic 33 potential, but also three-year recurrence rates.19 34 35 The main objective of this pilot trial, will be to assess the safety of the combination therapy with 36 propranolol and etodolac in the perioperative setting of pancreatic cancer surgery. Beyond safety, 37 http://bmjopen.bmj.com/ 38 feasibility will be analyzed, since the two predominant factors for curative treatment (surgery and 39 adjuvant chemotherapy) must not be affected by the above-mentioned drug administration. If the trial 40 41 treatment proves to be safe and feasible, the survival data derived from the current trial will form the 42 43 basis for a subsequent confirmatory phase-3 trial assessing its efficacy. 44 45 on September 28, 2021 by guest. Protected copyright. 46 METHODS AND ANALYSIS 47 Study design 48 49 The PROSPER-trial is a two-arm randomized, patient and observer blinded, placebo-controlled, phase-2 50 51 trial. The primary objective is to evaluate safety and feasibility of perioperative propranolol and etodolac 52 treatment in patients with resectable cancer of the pancreatic head planned for elective 53 54 pancreatoduodenectomy. Additionally, early parameters of efficacy will be assessed by analyzing 55 survival of the patients and by an ancillary translational study investigating the mechanisms of action of 56 57 the combined therapy on a molecular basis. The trial will be performed in a single-center setting at the 58 Department of General, Visceral and Transplantation Surgery of the University Hospital Heidelberg, 59 60 Germany, a center of excellence for pancreatic surgery with high volume in oncologic pancreatic

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1 2 3 surgery. Before inclusion of the first subject, the trial was registered with the German Clinical Trials BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Register (DRKS00014054). The full protocol and the current protocol publication were prepared in line 6 with the SPIRIT recommendations (Standard Protocol Items: Recommendations for Interventional 7 8 Trials).20 9 The two drugs under investigation, propranolol and etodolac, will be repurposed in the perioperative 10 11 setting of patients undergoing elective pancreatic head resection in order to potentially improve 12 13 oncological outcome by suppressing several pathways of systemic stress and inflammatory responses. 14 Eligible patients, who have provided written informed consent (for a model consent form see 15 16 supplementary file 1), will be randomized to either the combined drug therapy with propranolol and 17 etodolac, starting 10 days preoperatively until postoperative day 14, or corresponding placebo treatment. 18 For peer review only 19 Pancreatic resection and postoperative care will be performed according to local standards of the 20 Department of General, Visceral and Transplantation Surgery of the University Hospital Heidelberg.21 21 22 23 24 Study population and eligibility criteria 25 Patients with malignancy of the pancreatic head scheduled for elective pancreatoduodenectomy in 26 27 curative intent will be consecutively screened for eligibility according to the inclusion and exclusion 28 criteria that are listed in Box 1. Eligible patients will be informed verbally and in writing in 29 30 comprehensible language about the nature, scope and possible consequences of the trial by a trial 31 32 investigator. If a patient has provided written informed consent for trial participation (s)he will be 33 randomized to the verum or placebo group. Ineligible patients and those who refused to participate will 34 35 be documented in a screening log with the respective reason for non-participation. 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 Box 1. Major eligibility criteria of the trial 44 45 Inclusion criteria: on September 28, 2021 by guest. Protected copyright. 46 - Resectable malignancy of the pancreatic head, eligible for elective pancreatoduodenectomy 47 in curative intent 48 49 - WHO / ECOG performance status 0-2 50 51 - Age ≥ 18 years 52 - ASA score I-III 53 54 - Patient must be able to understand the consequences of trial participation and to provide 55 written informed consent 56 - Written informed consent from the trial subject has been obtained 57 58 - Female subject must be postmenopausal (for at least 6 months), surgically sterile, abstinent, 59 or, if sexually active, be practicing an effective method of birth control (e.g., prescription of 60 oral contraceptives, contraceptive injections, intrauterine device, double-barrier method,

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1 2 3 contraceptive patch, male partner sterilization) before entry and throughout the study; and BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 have a negative serum ß-hCG pregnancy test at screening 5 6 7 Exclusion criteria: 8 9 - Any contraindication for pancreatoduodenectomy 10 - Metastatic disease (Stage IV) 11 12 - Patients scheduled for palliative resection (no curative treatment intention) 13 14 - Patients scheduled for extended resections (i.e. arterial resections, planned multivisceral 15 resections) 16 - Acute or ongoing episode of cholangitis: fever and pain in the right upper quadrant of the 17 abdomen together with increased infectious parameters and elevated AP & GGT values 18 (alkaline phosphatase,For peer gamma glutamyl review transpeptidase) only > 3x upper limit of norm (ULN) 19 20 - Acute or ongoing episode of pancreatitis (clinical symptoms of pancreatitis, increased lipase 21 > 3x ULN and/or CRP values, radiological or intraoperative signs of acute pancreatitis) 22 - Chronic neuropathy > grade 2 23 24 - Renal failure, measured by GFR < 50 ml/min/1,73m2 (calculated according to CKD-EPI) 25 26 - Known liver cirrhosis of any grade 27 - Atrioventricular block 28 29 - Pregnant or breastfeeding women 30 - Mental or organic disorders, which could interfere with giving informed consent or receiving 31 treatments 32 33 - Any contraindication to propranolol and/or etodolac* 34 *for a list of all contraindications see supplementary file 2 35 36 37

Subject withdrawal http://bmjopen.bmj.com/ 38 39 Patients are free to leave the trial at any time and without giving reasons for their decision. Subjects may 40 be withdrawn from the trial for the following reasons: 41 42 a) at their own request, or 43 b) if, in the investigator’s opinion, continuation of the trial would be detrimental to the 44 45 subject’s well-being, e.g. symptomatic bradycardia after start of treatment, allergic reactions on September 28, 2021 by guest. Protected copyright. 46 47 to trial treatment, etc. In case of (b), the reason for withdrawal must be recorded in the case 48 report form (CRF) and in the patient’s medical records. 49 50 Patients, who withdrew or were withdrawn from the trial, will not be replaced. 51 52 53 Sample size 54 Since the current trial is conducted in an exploratory stage and not confirmatory, no formal sample size 55 56 calculation was performed. The sample size of 40 patients per group was judged to be sufficient for an 57 58 assessment of safety and feasibility by a panel of clinical and methodological experts at the 59 investigators’ institution. All analyses will be interpreted as exploratory. Considering a dropout rate of 60 approximately 20%, a total of 100 patients will be randomized within the trial. The estimated patient 6

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1 2 3 flow within the trial is depicted in figure 1. BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 Trial procedures 7 8 Perioperative combination therapy 9 There will be one experimental arm (A) and one control arm (B): 10 11 A. Propranolol + etodolac 12 13 B. Placebo 14 ARM A: Oral intake of propranolol 2 x 20 mg/day for 10 days preoperatively, 2 x 40 mg for the day of 15 16 surgery and one week after surgery, 2 x 20 mg for the second postoperative week combined with oral 17 intake of etodolac 2 x 400 mg/day for a total of 25 days perioperatively (starting at 10 days 18 For peer review only 19 preoperatively). The dosage is summarized in table 1. 20 ARM B: Oral intake of placebo tablets/capsules of the same appearance, size, and weight as propranolol 21 22 and etodolac. Placebo will be taken 2 x /day for a total of 25 days perioperatively (starting at 10 days 23 24 preoperatively). 25 26 27 28 29 30 31 32 33 34 35 Table 1: Dosage of trial medication 36 Time point Morning Evening 37 P 20 mg P 20 mg http://bmjopen.bmj.com/ 38 10 Preop. Days 39 E 400 mg E 400 mg 40 P 40 mg P 40 mg Day of surgery 41 E 400 mg E 400 mg 42 P 40 mg P 40 mg 43 POD 1 - 7 44 E 400 mg E 400 mg 45 P 20 mg P 20 mg on September 28, 2021 by guest. Protected copyright. POD 8 - 14 46 E 400 mg E 400 mg 47 48 P = propranolol or corresponding placebo; E = etodolac or corresponding placebo; POD: postoperative 49 day 50 51 52 With regard to current evidence and personal communications with experts on the combined 53 54 administration of propranolol and etodolac, we propose to use the dose of etodolac that was used by 55 Bhattacharyya et al. in their clinical trial in metastatic PDAC and in the perioperative trial in colorectal 56 57 cancer of Ben-Eliyahu and colleagues.22 23 Propranolol will be used in a standard dose of 2 x 20 mg, 58 59 which was also used by Ben-Eliyahu and colleagues in their colorectal cancer trial and an increased dose 60 of 2 x 40 mg on the day of surgery and the first postoperative week due to the increased stress factors

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1 2 3 in this period.23 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 22 5 Bhattacharyya et al. observed no treatment-associated serious adverse events. Equally, in the 6 perioperative colorectal cancer trial the combination therapy appeared safe with only one case of 7 8 symptomatic bradycardia that led to exclusion of the patient and two cases of tolerable bradycardia. 9 There were no differences in the rate of post-operative adverse events between the treatment and the 10 11 placebo groups.23 12 13 No dose adjustments are planned in individual subjects. In cases that require a temporary discontinuation 14 of trial treatment (e.g. swallowing of tablets not possible due to severe gastroparesis; treatment on 15 16 intensive care unit with e.g. catecholamine therapy; etc.), the treatment will be paused and resumed as 17 soon as possible if reasonable. The percentage of the finally taken medication from the planned 18 For peer review only 19 medication will be documented in the CRF (adherence). 20 In case of any acute deterioration of health by any cause, the patients can and will be treated by any 21 22 appropriate measures without restrictions. 23 24 25 Surgery and biospecimen collection 26 27 Partial pancreatoduodenectomy will be performed according to local standards at the Department of 28 General, Visceral and Transplantation Surgery of the Heidelberg University Hospital.21 Postoperative 29 30 care consists of a fast-track concept including a no-drain policy in routine cases, early mobilization and 31 32 early oral feeding. 33 For the translational part of the trial, peripheral blood samples will be collected during the screening 34 35 visit, the day before surgery, the day of surgery, on postoperative days (POD) 1, 3, 14 (or day of 36 discharge) and 3 months postoperatively. Additionally, portal venous blood will be taken 37 http://bmjopen.bmj.com/ 38 intraoperatively immediately after dissection of the hepatoduodenal ligament and before resection of the 39 tumor. Immediately after resection, a biopsy of 0.5-1cm3 will be excised from the resected 40 41 specimen for biobanking and molecular analysis in the translational part of the study. Detailed 42 43 methodology of the translational study will be described in a separate publication. 44 45 on September 28, 2021 by guest. Protected copyright. 46 Trial endpoints 47 Safety endpoints 48 49 Safety will be evaluated by the rates of serious adverse events (SAE) and serious adverse reactions in 50 51 the two treatment groups within a period of three months postoperatively. 52 Further measurements of safety include postoperative mortality within 30 and 90 days, pancreas- 53 54 associated morbidity, such as postoperative pancreatic fistula (POPF) according to the up-dated ISGPS 55 (International Study Group of Pancreatic Surgery) definition,24 delayed gastric emptying and 56 57 postpancreatectomy hemorrhage according to the respective ISGPS definitions,25 26 postoperative biliary 58 leakage according to the ISGLS (International Study Group of Liver Surgery) definition27 and 59 60 postoperative intra-abdominal fluid collection or abscess.

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1 2

3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Feasibility endpoints 6 Feasibility will be assessed by the evaluation of adherence to study medication intake. The rationale for 7 8 this endpoint is that there are some factors in the perioperative period, which might preclude patients 9 from taking the intended medication (e.g. delayed gastric emptying/gastroparesis, nausea/vomiting, 10 11 intolerable bradycardia under propranolol, etc.). This would hamper a wide-spread implementation into 12 13 treatment protocols. Adherence to study medication will thus provide more insight into the feasibility 14 of implementing treatment with propranolol and etodolac into perioperative treatment plans. Adherence 15 16 to trial medication will be documented in a medication diary. Every patient will be asked to document 17 his drug intake or any impediments. Furthermore, all used or unused blister packs will need to be turned 18 For peer review only 19 in to the trial center by the patients. Opened packages with left-over investigational medicinal product 20 (IMPs) will be accounted for at the trial center. The percentage of the finally taken medication from the 21 22 planned medication will be documented in the electronic case report form (eCRF). 23 24 Furthermore, completion of adjuvant chemotherapy will be evaluated as another measure of feasibility. 25 This endpoint provides further insight into the practicality of implementing the trial intervention into 26 27 modern routine treatment schedules. 28 29 30 Efficacy endpoints 31 32 Overall and disease-free survival will be assessed as oncologic long-term variables. Survival is the 33 ultimate goal of any cancer directed therapy. Apart from overall survival, disease-free survival has been 34 35 proven to be a reliable parameter in phase II/III clinical trials. 36 Furthermore, rates of local and distant recurrence will be assessed as another efficacy outcome. 37 http://bmjopen.bmj.com/ 38 39 Biological endpoints 40 41 Biological endpoints/Biomarkers will be measured at different timepoints of study conduct as described 42 43 above. The following parameters will be assessed: 44 Blood samples: 45 on September 28, 2021 by guest. Protected copyright. 46 1. Routine laboratory biomarkers: differential blood count, c-reactive protein (CRP), 47 albumin, carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) 48 49 2. Translational study biomarkers: phenotyping of circulating immune cells (FACS), 50 51 cytokine multiplex, PGE-2 levels, circulating tumor cells, RNA sequencing in periphery blood 52 cells (leukocytes) 53 54 Tissue samples (translational part of the study): 55 1. Biomarkers associated with COX-2 inhibition: COX-2, PGE-2, interleukin 6 (IL-6) 56 57 expression 58 59 60

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1 2 3 2. Biomarkers associated with β-blockade: adrenoceptor beta 2 (ADRB2), vascular BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2), matrix 6 metalloproteinase 4 (MMP4), S100, brain-derived neurotrophic factor (BDNF) expression 7 8 3. Characterization of the immune cell infiltrate (IHC) 9 4. RNA sequencing of bulk tissue or of sorted tumor and stromal cells 10 11 In addition, tumor cells will be cultures as organoids for further biological substudies. 12 13 14 Table 2 gives an overview of the clinical trial visits and displays which endpoints will be captured during 15 16 the respective visits. 17 18 For peer review only 19 Table 2: Trial visits and assessment of endpoints 20 Visit Visit Visit Visit Visit 21 Documentation Visit 2 Visit 3 Visit 8 Visit 9 1 4-6 7 10 11-13 22 23 24 25 26 POD 27 1/3/5 6/12/ POD 7 POD 30 3 months Screening 28 24 months

29 Day of surgery POD 14/ discharge Day before surgery 30 10-28daysafter V1 31 Eligibility criteria X X 32 Baseline data, 33 X 34 demographics 35 Randomization X 36 Previous 37 X

medication http://bmjopen.bmj.com/ 38 Assessment X X X X X X X 39 of safety 40 Feasibility / X X X X X X X 41 adherence 42 Secondary X X X X X 43 endpoints* 44 Survival/ X§ X§ X§ X§ X§ X§ X X 45 recurrence on September 28, 2021 by guest. Protected copyright. 46 Routine blood X X X X X 47 sampling† 48 Blood sampling X X X X‡ X X 49 translational tests 50 Tissue sampling X 51 * 52 details of surgery, pathologic results (TNM stage), pancreas specific complications 53 † blood count, CRP, creatinin, bilirubin, albumin, international normalized ratio (INR), CEA, CA 19-9 54 55 (Visit 1 and/or 2, 10), pregnancy test in case of childbearing potential (Visit 1) 56 ‡ POD 1 and 3 only 57 58 § only survival 59 60

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1 2 3 Safety objectives and assessment of safety BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 All patients will be closely monitored for the occurrence of adverse events (AE). In this trial, all adverse 6 events will be documented from the first administration of the investigational medicinal products (10 7 8 days prior to surgery) until 3 months postoperatively. An AE is any untoward medical occurrence in a 9 trial subject administered an investigational medicinal product. There does not necessarily have to be a 10 11 causal relationship with the investigational medicinal product or any other trial-related procedure. A 12 13 serious adverse event (SAE) or serious adverse reaction (SAR) is any untoward medical occurrence, 14 without or with a reasonably possible causal relationship with the IMP, that at any dose: 15 16 1. results in death, 17 2. is life-threatening at the time of the event, 18 For peer review only 19 3. requires inpatient hospitalization or prolongation of existing hospitalization, 20 4. results in persistent or significant disability/incapacity, 21 22 5. is a congenital anomaly or birth defect, 23 24 6. is, in the opinion of the investigator, otherwise medically relevant (e.g. requiring re- 25 laparotomy, endoscopic treatment or interventional percutaneous drainage, etc.). 26 27 Preexisting diseases are not documented as AE but as concomitant diseases. New diseases or 28 deteriorations of preexisting illnesses are also an AE in the context of this clinical trial. However, a 29 30 preexisting disease that leads to a treatment measure, which has already been planned before the start of 31 32 the clinical trial, is not regarded as an AE or SAE. Furthermore, changes of a preexisting disease, which 33 represent the natural/expectable course of the disease are not regarded an AE. Routine medical treatment 34 35 after pancreatoduodenectomy will not be regarded as AE. In the postoperative period, expectable clinical 36 and/or laboratory findings (e.g. postoperative pain, delayed reuptake of bowel function, increase of CRP 37 http://bmjopen.bmj.com/ 38 and white blood cells, decrease of Hb-value, increase of liver function parameters, etc.) will not be 39 regarded as (S)AE as long as they are without deviation from the expectable clinical course. A list of 40 41 the expectable changes is included in the full trial protocol and can be obtained upon request from the 42 43 corresponding author. 44 The Data Safety Monitoring Board will receive listings of all SAE after the accrual of 20, 40 and 60 45 on September 28, 2021 by guest. Protected copyright. 46 patients for review and assessment of patient risk and potential differences between the trial groups. 47 The Coordination Center for Clinical Trials (KKS) Heidelberg will be responsible for 48 49 pharmacovigilance and will provide a development safety update report once a year prepared according 50 51 to the International Council for Harmonisation (ICH) guideline E2F. 52 53 54 Ancillary translational study 55 In addition to routine blood sampling, which includes blood count, CRP, creatinine, bilirubin, albumin 56 57 and INR, blood samples for translational tests will be taken at the above-mentioned points of time. The 58 translational tests will consist of a cytokine multiplex (screening visit and day before surgery), PGE-2 59 60 levels (screening visit and day before surgery), circulating tumor cells (POD 3), RNA sequencing in

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1 2 3 periphery blood cells (leukocytes; POD 3). The tumor tissue, which is sampled at surgery, will be BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 investigated by tissue cultures (organoids and pluripotent stem cells). Furthermore, COX-2 expression, 6 PGE-2 levels and immune cell infiltration will be investigated and RNA sequencing of bulk tissue or of 7 8 sorted tumor and stromal cells will be performed. 9 10 11 Data handling and monitoring 12 13 An investigator or a designated representative will enter all protocol-required data into the eCRF. All 14 entries in the eCRF must be verifiable by source documents. Data entries will undergo an automatic 15 16 online check for plausibility and consistency. Upon completion of the eCRF, the investigator has to 17 confirm the accuracy of all data by signing sections online in the eCRF. 18 For peer review only 19 On site visits will be done by the monitor at regular intervals to ensure compliance with the trial protocol, 20 ICH good clinical practice (GCP) guidelines and legal aspects. The monitor must be given access to all 21 22 trial relevant documents by the investigator. He will review the entries into the eCRF for completeness 23 24 and correctness and verify the entries on the basis of the source documents. The responsible monitor 25 and the data manager can generate special questions (queries) that will be sent back to the responsible 26 27 investigator. The investigator or a designated representative will have to answer them all in a timely 28 manner. 29 30 Data management and monitoring activities will be performed according to the current standard 31 32 operating procedures of the Coordination Center for Clinical Trials (KKS) or the Study Center of the 33 German Surgical Society (SDGC) respectively. 34 35 36 Statistical analysis 37 http://bmjopen.bmj.com/ 38 The main safety, feasibility and efficacy variables will be analyzed with generalized linear models or 39 Cox regression models. Parameter estimates from these models will be reported with 95 percent profile 40 41 likelihood-based confidence intervals. All other variables will be tabulated by treatment group using 42 number of missing and non-missing values, the quartiles, mean and standard deviation. 43 44 All subjects who have ever been randomized to study treatment will form the full analysis set for efficacy 45 on September 28, 2021 by guest. Protected copyright. 46 purposes. All patients will be analyzed according to the treatment group they have been randomized to, 47 regardless of the treatment they actually received (intention-to-treat). A restricted full analysis set will 48 49 be formed by the set of subjects undergoing surgical resection of the pancreas. Patients not undergoing 50 surgery at all or patients, who did not take at least 50% of their preoperative trial medication will be 51 52 replaced. The per-protocol set will comprise all patients receiving at least 75% per cent of study 53 54 medication at the appropriate time points. The safety set will contain all patients ever receiving study 55 medication and will assign patients to treatment group according to the treatment they actually received. 56 57 Analysis with respect to the main safety endpoints will be conducted using the safety set. Feasibility 58 will be compared using the full analysis set, whereas analysis on efficacy will be conducted using the 59 60 restricted full analysis set. A sensitivity analysis for efficacy will be per-formed for the per protocol set.

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1 2 3 The rate of SAE/SAR will be used as the primary safety variable. It will be analyzed using a Poisson BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 regression model using the time under risk as an offset and treatment group as an explanatory variable. 6 7 8 Methods for minimizing bias 9 Minimizing selection bias: Patients will be consecutively screened and all eligible patients will be asked 10 11 for informed consent. All patients who have been screened but not included into the trial, will be 12 13 documented together with the respective reason for exclusion to assure transparency regarding patient 14 selection. Included patients will be allocated concealed by 1:1 randomization using a random list. Block 15 16 randomization of variable sizes will be performed. 17 The pharmacy will manufacture consecutively numbered packages of trial medication of either verum 18 For peer review only 19 or placebo according to the random list and deliver these to the trial center on demand. On inclusion of 20 a new subject, the investigator or designated representative (e.g. a study nurse) will hand out the package 21 22 with the lowest remaining number to the patient and inform the monitoring about every new 23 24 randomization. 25 Minimizing performance and detection bias: Patients as well as all trial will be blinded with regard to 26 27 the trial drugs by means of placebo drugs in the control group. Since standard treatment is no specific 28 perioperative medication and no proven treatment during this period exists, which may improve 29 30 survival, the use of placebo is justified. Therefore, patients with placebo treatment will not be at risk of 31 32 harm. 33 If it is medically imperative to know whether the patient receives verum or placebo, the investigator or 34 35 an authorized person should break the randomization code for the concerned patient. The investigator 36 or the person, who breaks the blind, must record the date and the reason for unblinding in the subject’s 37 http://bmjopen.bmj.com/ 38 medical record and in the randomization tool. Whenever possible, the principal investigator should be 39 contacted before the blind is broken. 40 41 Minimizing attrition and reporting bias: The trial will be reported according to the CONSORT 42 28 43 statement and to minimize reporting bias the trial was registered in advance in the German Clinical 44 Trials Registry DRKS (DRKS00014054), an approved Primary Register of the WHO International 45 on September 28, 2021 by guest. Protected copyright. 46 Clinical Trials Registry Platform meeting the requirements of the International Committee of Medical 47 Journal Editors. For transparency regarding conduct and reporting of this trial, the protocol is hereby 48 49 published according to the SPIRIT statement.20 50 51 52 Ethics and regulatory aspects 53 54 Ethical basis for this trial are the principles described in the applicable version of the Declaration of 55 Helsinki.29 The present trial is conducted in accordance with the internationally recognized Good 56 57 Clinical Practice Guidelines (ICH-GCP), national regulatory requirements like the German Drug Law 58 (AMG) and German GCP Regulation, as well as the European regulations Directive 2001/20/EC and 59 60 Commission Directive 2005/28/EC.

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1 2 3 Before start of the clinical trial, the trial was registered with EudraCT (2018-000415-25) and in the BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 German Clinical Trials Registry (DRKS00014054). The trial was approved by the competent authority, 6 the German Federal Institute for Drugs and Medical Devices (reference number 4042875 on August 28th 7 8 2018). Furthermore, the trial was reviewed by the Ethics Committee of the Medical Faculty of the 9 University of Heidelberg and was positively evaluated (reference number AFmo-385/2018 on August 10 11 10th 2018). 12 13 Data protection laws (Bundesdatenschutzgesetz and Landesdatenschutzgesetz Baden-Württemberg) as 14 well as the provisions of the General Data Protection Regulation (Regulation 2016/679 of the European 15 16 Union) will be respected. It is assured by the sponsor that all investigational materials and data will be 17 pseudonymized in accordance with data protection legislation before scientific processing. 18 For peer review only 19 Trial drugs are licensed within the EU and dosage for each drug lies within the licensing 20 recommendations. For the combination propanolol/etodolac data have been published documenting 21 22 good tolerance. Exclusion criteria will guarantee that patients with preexisting severe diseases are 23 24 excluded. Therefore, the risk-benefit ratio for this selected patient group is positive. 25 Patients may not be enrolled into the present trial unless they have consented to take part in the trial 26 27 after having been informed verbally and in writing in comprehensible language of the nature, scope and 28 possible consequences by a trial investigator. Together with the consent to take part in the trial, the trial 29 30 subject must also agree to representatives of the sponsor (e.g. monitors or auditors) or the competent 31 32 supervisory or federal authorities having access to the data recorded within the framework of the clinical 33 trial. The trial subject will be informed of the potential benefit and possible side effects of the IMP and 34 35 placebo, and of the need and rea-sons to conduct a placebo-controlled clinical trial. It must be clear to 36 trial subjects that he or she can withdraw his or her consent at any time without giving reasons and 37 http://bmjopen.bmj.com/ 38 without jeopardizing his / her further course of treatment. 39 40 41 Amendments to the trial protocol 42 43 Amendments made in accordance with § 10 Secs. 1 and 4 GCP Regulations that require approval are 44 submitted to the ethics committee and the federal higher authority and will not be implemented until 45 on September 28, 2021 by guest. Protected copyright. 46 approved. 47 Since the start of the PROSPER trial, two amendments have been implemented and have been approved. 48 49 These included two relevant changes to the eligibility criteria: the exclusion criterion “Pre-operative CA 50 51 19-9 > 400 U/ml” was deleted during the first amendment and the exclusion criterion “Previous 52 neoadjuvant therapy” was deleted during the second amendment. This included the addition of a 53 54 subgroup analysis regarding efficacy of patients with vs. without neoadjuvant therapy. Furthermore, 55 details on neoadjuvant treatment (treatment protocol, dosage, etc.) will be documented together with the 56 57 baseline characteristics upon inclusion into the trial. Additionally, the amendments comprised only 58 minor changes and precisions, e.g. regarding the amount of blood sampled during the translational tests. 59 60

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1 2 3 Patient and public involvement BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Patients or the public were not directly involved in the development of this trial protocol. However, our 6 group conducted a priority setting partnership on pancreatic cancer identifying the most important 7 8 research questions by a priority setting group composed of patients, caregivers, members of patient 9 support groups and health-care professionals. The generated top ten list of research priorities included 10 11 several aspects that are addressed by this trial, e.g. “How can the best treatment for each individual 12 30 13 patient with PC be identified?”. Additionally, it is planned to distribute the results of this trial after its 14 completion within patient support groups such as the German “Arbeitskreis der Pankreatektomierten 15 16 e.V.”. 17 18 For peer review only 19 Dissemination 20 It is planned to publish the trial results of this trial in a scientific, peer-reviewed journal and to present 21 22 the results at appropriate national or international scientific conferences. 23 24 Results from the accompanying translational part of the study will be published in mutual agreement 25 with the principal investigator of the clinical trial and the responsible investigator of the translational 26 27 study. 28 A full deidentified individual patient dataset of the trial will be made available after trial completion and 29 30 publication upon reasonable request from the corresponding author. 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Author contributions BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 FJH, IR, GB, PK, JH, ALM, OS and MKD designed the study protocol. All authors contributed to the 6 study design. FJH, IR, GB, OS, MWB and MKD initiated this clinical study. FJH and MKD wrote the 7 8 paper. All authors approved the final version of this manuscript. All authors agreed to be accountable 9 for all aspects of the work, and ensure that any questions related to the accuracy or integrity of any 10 11 part of the work will be appropriately investigated and resolved. 12 13 14 Funding statement 15 16 This clinical trial is financed with donations of Het Anti-Kankerfonds (Anticancer Fund), a Belgian- 17 based private foundation (grant number: A56). No commercial stakeholder was involved in the 18 For peer review only 19 planning or conduct of this trial. 20 21 22 Disclaimer 23 24 The funding source of the trial does not have a role in data collection, data analysis, or interpretation 25 of the trial results. 26 27 28 Competing interests statement 29 30 None declared. 31 32 33 Trial status 34 35 The first patient was included on January 11th 2019. Recruitment is currently ongoing. 36 37 http://bmjopen.bmj.com/ 38 Acknowledgements 39 We thank Inga Rossion (SDGC) and Liese Vandeborne (Anticancer Fund) for their ongoing support 40 41 regarding this trial in various aspects. Additionally, we appreciate the work of all contributors from the 42 43 Anticancer Fund, the KKS, the SDGC as well as from the clinical study center of the Department of the 44 General, Visceral and Transplantation Surgery of the University Heidelberg. Furthermore, we want to 45 on September 28, 2021 by guest. Protected copyright. 46 acknowledge the honorary work of the members of the DSMB: Richard Jackson, Cancer Research UK 47 Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, United Kingdom; Paul Karanicolas 48 49 (Sunnybrooke Health Sciences Centre, Toronto, Ontario, Canada); Erica Sloan (Institute of 50 51 Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 52 53 54 55 56 57 58 59 60

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1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 1. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Lyon, France: 5 International Agency for Research on Cancer; 2018 [Available from: https://gco.iarc.fr/today 6 accessed 13-OCT-2019. 7 2. Arnold M, Rutherford M, Lam F, Bray F, Ervik M, Soerjomataram I. ICBP SURVMARK-2 online 8 tool: International Cancer Survival Benchmarking. Lyon, France.: International Agency for 9 Research on Cancer; 2019 [Available from: http://gco.iarc.fr/survival/survmark accessed 05 10 APR 2020. 11 12 3. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Tomorrow. Lyon, France.: 13 International Agency for Research on Cancer.; 2018 [Available from: 14 https://gco.iarc.fr/tomorrow accessed 05 April 2020. 15 4. Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet 2016;388(10039):73-85. doi: 16 10.1016/S0140-6736(16)00141-0 [published Online First: 2016/02/03] 17 5. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for 18 Pancreatic Cancer.For N Engl peer J Med 2018;379(25):2395-406. review only doi: 10.1056/NEJMoa1809775 19 [published Online First: 2018/12/24] 20 6. Hiller JG, Perry NJ, Poulogiannis G, Riedel B, Sloan EK. Perioperative events influence cancer 21 recurrence risk after surgery. Nat Rev Clin Oncol 2018;15(4):205-18. doi: 22 10.1038/nrclinonc.2017.194 [published Online First: 2017/12/29] 23 7. Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK. Sympathetic nervous system 24 regulation of the tumour microenvironment. Nat Rev Cancer 2015;15(9):563-72. doi: 25 10.1038/nrc3978 [published Online First: 2015/08/25] 26 8. Horowitz M, Neeman E, Sharon E, Ben-Eliyahu S. Exploiting the critical perioperative period to 27 improve long-term cancer outcomes. Nat Rev Clin Oncol 2015;12(4):213-26. doi: 28 10.1038/nrclinonc.2014.224 [published Online First: 2015/01/21] 29 9. Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer 2010;10(3):181-93. doi: 30 31 10.1038/nrc2809 [published Online First: 2010/02/20] 32 10. Mao Y, Sarhan D, Steven A, Seliger B, Kiessling R, Lundqvist A. Inhibition of tumor-derived 33 prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and recovers 34 natural killer cell activity. Clin Cancer Res 2014;20(15):4096-106. doi: 10.1158/1078- 35 0432.CCR-14-0635 [published Online First: 2014/06/08] 36 11. Zelenay S, van der Veen AG, Bottcher JP, et al. Cyclooxygenase-Dependent Tumor Growth 37 through Evasion of Immunity. Cell 2015;162(6):1257-70. doi: 10.1016/j.cell.2015.08.015 http://bmjopen.bmj.com/ 38 [published Online First: 2015/09/08] 39 12. Karnezis T, Shayan R, Caesar C, et al. VEGF-D promotes tumor metastasis by regulating 40 prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 41 2012;21(2):181-95. doi: 10.1016/j.ccr.2011.12.026 [published Online First: 2012/02/22] 42 13. Kumar P, Shen Q, Pivetti CD, Lee ES, Wu MH, Yuan SY. Molecular mechanisms of endothelial 43 hyperpermeability: implications in inflammation. Expert Rev Mol Med 2009;11:e19. doi: 44 10.1017/S1462399409001112 [published Online First: 2009/07/01] 45 14. Le CP, Nowell CJ, Kim-Fuchs C, et al. Chronic stress in mice remodels lymph vasculature to on September 28, 2021 by guest. Protected copyright. 46 promote tumour cell dissemination. Nat Commun 2016;7:10634. doi: 10.1038/ncomms10634 47 [published Online First: 2016/03/02] 48 15. Bertolini F, Sukhatme VP, Bouche G. Drug repurposing in oncology--patient and health systems 49 opportunities. Nat Rev Clin Oncol 2015;12(12):732-42. doi: 10.1038/nrclinonc.2015.169 50 51 [published Online First: 2015/10/21] 52 16. Pantziarka P, Verbaanderd C, Sukhatme V, et al. ReDO_DB: the repurposing drugs in oncology 53 database. Ecancermedicalscience 2018;12:886. doi: 10.3332/ecancer.2018.886 [published 54 Online First: 2019/01/27] 55 17. Ricon I, Hanalis-Miller T, Haldar R, Jacoby R, Ben-Eliyahu S. Perioperative biobehavioral 56 interventions to prevent cancer recurrence through combined inhibition of beta-adrenergic and 57 cyclooxygenase 2 signaling. Cancer 2019;125(1):45-56. doi: 10.1002/cncr.31594 [published 58 Online First: 2018/10/07] 59 18. Sorski L, Melamed R, Matzner P, et al. Reducing liver metastases of colon cancer in the context of 60 extensive and minor surgeries through beta-adrenoceptors blockade and COX2 inhibition.

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1 2 3 Brain Behav Immun 2016;58:91-98. doi: 10.1016/j.bbi.2016.05.017 [published Online First: BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 2016/05/29] 5 19. Haldar R, Ricon-Becker I, Radin A, et al. Perioperative COX2 and beta-adrenergic blockade 6 improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A 7 randomized controlled trial. Cancer 2020 doi: 10.1002/cncr.32950 [published Online First: 8 2020/06/14] 9 20. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol 10 items for clinical trials. Ann Intern Med 2013;158(3):200-7. doi: 10.7326/0003-4819-158-3- 11 12 201302050-00583 [published Online First: 2013/01/09] 13 21. Schneider M, Strobel O, Hackert T, Buchler MW. Pancreatic resection for cancer-the Heidelberg 14 technique. Langenbecks Arch Surg 2019;404(8):1017-22. doi: 10.1007/s00423-019-01839-1 15 [published Online First: 2019/11/16] 16 22. Bhattacharyya GS, Babu KG, Bondarde SA, et al. Effect of coadministered beta blocker and COX- 17 2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) 18 paclitaxel. J ClinFor Oncol peer 2015;33 review only 19 23. Zmora O, Shaashua L, Gutman M, Ben-Eliyahu S. The perioperative use of a beta-adrenergic 20 blocker and a COX-2 inhibitor in colorectal cancer patients for the prevention of cancer 21 recurrence: A preliminary study assessing feasibility and safety. Brain, Behavior, and 22 Immunity 2016;57 23 24. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group 24 (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After. Surgery 25 2017;161(3):584-91. doi: 10.1016/j.surg.2016.11.014 [published Online First: 2017/01/04] 26 25. Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a 27 suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 28 2007;142(5):761-8. doi: 10.1016/j.surg.2007.05.005 [published Online First: 2007/11/06] 29 26. Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage (PPH): an International Study 30 31 Group of Pancreatic Surgery (ISGPS) definition. Surgery 2007;142(1):20-5. doi: 32 10.1016/j.surg.2007.02.001 [published Online First: 2007/07/17] 33 27. Koch M, Garden OJ, Padbury R, et al. Bile leakage after hepatobiliary and pancreatic surgery: a 34 definition and grading of severity by the International Study Group of Liver Surgery. Surgery 35 2011;149(5):680-8. doi: 10.1016/j.surg.2010.12.002 [published Online First: 2011/02/15] 36 28. Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: updated guidelines for 37 reporting parallel group randomised trials. BMJ 2010;340:c332. doi: 10.1136/bmj.c332 http://bmjopen.bmj.com/ 38 [published Online First: 2010/03/25] 39 29. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles 40 for medical research involving human subjects. JAMA 2013;310(20):2191-4. doi: 41 10.1001/jama.2013.281053 [published Online First: 2013/10/22] 42 30. Klotz R, Doerr-Harim C, Ahmed A, et al. Top ten research priorities for pancreatic cancer therapy. 43 Lancet Oncol 2020;21(6):e295-e96. doi: 10.1016/S1470-2045(20)30179-0 [published Online 44 First: 2020/06/06] 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Page 21 of 43 BMJ Open Assessed for eligibility 1 n = 480 2 Patients with resectable carcinoma of the pancreatic head 3 planned for pancreatoduodenectomy 4 5 Excluded n = 380 6 - Not meeting eligibility criteria 7 Enrolment - Declined to participate 8 - Other reasons 9 10 Visit 1 11 Eligible patients with written informed consent 12 13 For peerTo be randomized review n = 100 only 14 15 16 17 18 Treatment group Placebo control group Excluded 19 (Propranolol + etodolac) N = 10 20 (no intake of 21 n = 50 n = 50 trial drugs, no 22 Allocation 23 operation) 24 Visit 2 OP Day - 1 OP Day - 1 25 26

27 http://bmjopen.bmj.com/ Visit 3 OP Day OP Day 28 29 30 31 Visit 4 - 6 POD 1/ 3/ 5 POD 1/ 3/ 5 32 33 34 Visit 7 POD 7 POD 7

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9 Chirurgische Klinik Chirurgische Universitätsklinik ó Im Neuenheimer Feld 110 ó 69120 Heidelberg 10 Klinik für Allgemein-, Viszeral- 11 und Transplantationschirurgie 12 Studienleiter 13 Prof. Dr. M.W. Büchler Prof. Dr.med. Markus K. Diener Ärztlicher Direktor 14 15 ( +49 6221 56 6200 +49 6221/56-6111 Pforte 16 Studienkontakt +49 6221 56 5450 17 Klinisches Studienzentrum KSC [email protected] 18 Tel.: 06221 / 56-36209For peer review only heidelberg.de 19 www.ukl.uni-heidelberg.de/chir

20 21 22 23 24 Patienteninformation und Einwilligung 25 26 27 PROSPER Studie 28 29 Randomisierte Phase II–Studie zur perioperativen Off-Label Behandlung mit Propranolol und 30 Etodolac im Rahmen von Bauchspeicheldrüseneingriffen 31 32 33 Englischer Titel: PANCREATIC RESECTION WITH PERIOPERATIVE OFF-LABEL STUDY OF PROPRANOLOL AND 34 ETODOLAC – A PHASE II RANDOMIZED TRIAL 35 36 37 http://bmjopen.bmj.com/ 38 Sehr geehrte Patientin, sehr geehrter Patient, 39 40 wir möchten Sie fragen, ob Sie bereit sind, an der nachfolgend beschriebenen klinischen 41 Prüfung (Studie) teilzunehmen. 42 43 Ihre Teilnahme ist freiwillig. Sie werden also nur dann in diese Studie einbezogen, wenn Sie 44 hierzu schriftlich Ihre Einwilligung erklären. Sofern Sie nicht an der klinischen Prüfung 45 teilnehmen oder zu einem späteren Zeitpunkt ausscheiden möchten, erwachsen Ihnen daraus on September 28, 2021 by guest. Protected copyright. 46 keine Nachteile. 47 48 Sie wurden bereits auf die geplante Studie angesprochen. Der nachfolgende Text soll Ihnen 49 die Ziele und den Ablauf erläutern. Anschließend wird ein Prüfarzt das Aufklärungsgespräch 50 51 mit Ihnen führen. Bitte zögern Sie nicht, alle Punkte anzusprechen, die Ihnen unklar sind. 52 Sie werden danach ausreichend Bedenkzeit erhalten, um über Ihre Teilnahme zu 53 entscheiden. 54 55 Die PROSPER Studie wurde von der zuständigen Ethikkommission positiv bewertet und von 56 der Arzneimittelüberwachungsbehörde (BfArM) genehmigt. Sie wird in Heidelberg, an der 57 Klinik für Allgemein-, Viszeral- und Transplantationschirurgie durchgeführt. Studienleiter ist 58 59 Prof. Dr. med. Markus K. Diener, Erster Oberarzt der Klinik, und das Universitätsklinikum 60 Heidelberg hat als Sponsor die Gesamtverantwortung für die Studie. Insgesamt sollen unge- fähr 80 Patienten an der PROSPER Studie teilnehmen.

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9 10 11 Finanziert wird die Studie vom Anticancer Fund in Belgien, einer gemeinnützigen Stiftung, 12 die sich der Krebsforschung widmet. 13 14 15 1. Warum wird diese Prüfung durchgeführt? 16 17 Bei Ihnen wurde eine bösartige Erkrankung der Bauchspeicheldrüse festgestellt, und nun ist 18 For peer review only 19 als Therapie eine chirurgische Entfernung (Resektion) des veränderten Gewebes geplant. 20 Eine ausführliche separate Aufklärung zu dieser Operation haben Sie schon oder werden Sie 21 22 noch von Ihrem behandelnden Arzt erhalten. Trotz Operation besteht bei bösartigen 23 Erkrankungen leider immer das Risiko, dass die Krankheit nach einiger Zeit wieder auftreten 24 kann. Eine schwere Erkrankung wie sie bei Ihnen festgestellt wurde, erzeugt psychischen und 25 körperlichen Stress und auch Operationen führen zu einer Entzündungs- und Stressreaktion 26 27 im Körper. Diese Reaktionen können das Risiko für einen Rückfall der Erkrankung erhöhen. 28 Von den in der Studie eingesetzten Arzneimitteln ist bekannt, dass Sie die negativen Folgen 29 30 von Entzündungs- und Stressreaktionen vermindern können. Daher wollen wir mit dieser 31 Studie untersuchen, welche Wirkungen und Nebenwirkungen mit der kombinierten 32 Einnahme der beiden Medikamente bei Ihrer Erkrankung verbunden sind und, ob diese in 33 der Zeit vor und nach der Operation wie vorgesehen eingenommen werden können. 34 35 Außerdem erhoffen wir uns erste Aussagen darüber machen zu können, ob durch die 36 Einnahme die krankheitsfreie Zeit verlängert oder ein Rückfall verhindert werden kann. 37 http://bmjopen.bmj.com/ 38 39 2. Welche Medikamente werden eingesetzt? 40 41 Etodolac und Propranolol sind Arzneimittel, die bereits seit Jahren zugelassen sind, d.h. ihre 42 Wirkungen und Nebenwirkungen sind bestens bekannt. Bei Propranolol handelt es sich um 43 44 einen der ältesten und am meisten verordneten Betablocker, der vor allem zur Behandlung 45 von Bluthochdruck oder anderen Herz-Kreislauferkrankungen eingesetzt wird. Etodolac ist ein on September 28, 2021 by guest. Protected copyright. 46 entzündungshemmendes Schmerzmittel und ebenfalls in vielen Ländern Europas zugelassen. 47 Die Kombination der beiden Arzneimittel wurde bereits in mehreren Studien bei Patienten mit 48 49 Darm- und Brustkrebs untersucht. Da die positive Beeinflussung der krankheitsfreien Zeit 50 durch die entzündungs- und stressreduzierende Wirkung jedoch ein neues Behandlungsfeld 51 der Medikamentenkombination wäre, sind weitere Studien erforderlich. 52 53 Wenn Sie an der Studie teilnehmen, dann nehmen Sie für 10 Tage vor der Operation, am 54 Operationstag sowie zwei Wochen danach morgens und abends jeweils zwei Tabletten und 55 eine Kapsel ein. Dabei handelt es sich entweder um die beiden Medikamente Etodolac und 56 57 Propranolol oder um gleich aussehende Placebotabletten und –kapseln, die keinen Wirkstoff 58 enthalten. 59 60 Durch den Vergleich gegenüber einem Placebo können die Wirkungen und Nebenwirkungen der Therapie gegenüber der Vergleichsgruppe besser beurteilt werden, da hierdurch eine

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9 sogenannte „Verblindung“ möglich ist, die eine unabhängige Beurteilung durch das 10 11 Studienpersonal ermöglicht. Dieses Vorgehen ist Standard in Arzneimittelstudien, weil 12 hierdurch weitere Einflussfaktoren auf die Wirkung ausgeschlossen werden können. Sollte es 13 aus Sicherheitsgründen notwendig sein, kann unverzüglich festgestellt werden, welches 14 Medikament Sie erhalten haben. 15 16 Welche der Behandlungen Sie erhalten, entscheidet ein unabhängig festgelegtes 17 Zufallsverfahren, das Randomisation genannt wird. In dieser Studie wird jeweils die Hälfte der 18 For peer review only 19 Patienten Propranolol und Etodolac erhalten bzw. das Placebo. Die Wahrscheinlichkeit, dass 20 Sie Propranolol und Etodolac erhalten, beträgt somit 50 %. 21 22 23 3. Wie ist der Ablauf der Studie und was muss ich bei Teilnahme beachten? 24 25 Für die Aufnahme in die Studie sind keine zusätzlichen Voruntersuchungen notwendig. 26 27 Insgesamt 25 Tage lang müssen Sie täglich morgens und abends je zwei Tabletten und je eine 28 Kapsel schlucken. Die Blisterverpackungen der Medikamente müssen aufgehoben und am 29 30 Ende der Einnahmeperiode zurückgegeben oder –geschickt werden (Freiumschlag). Außerdem 31 erhalten Sie ein Patiententagebuch, in dem Sie die Medikamenteneinnahme und eventuelle 32 Besonderheiten notieren. 33 Ihren Hausarzt informieren wir mit einem Schreiben über Ihre Studienteilnahme. 34 35 Zu sechs Zeitpunkten (Studieneinschluss, Tag vor der OP, am OP-Tag,1. und 3. Tag nach der 36 OP, Tag der Entlassung bzw. spätestens Tag 14 nach der OP und 3 Monate nach der OP) 37 http://bmjopen.bmj.com/ 38 werden wir jeweils ca. 30-38 ml (und am OP-Tag einmalig 70 ml) Blut, also im Verlauf der 39 Studie insgesamt 282 ml, abnehmen. Die Entnahme erfolgt zusammen mit einer 40 Routineblutentnahme, so dass Sie keine zusätzlichen Schmerzen oder Unannehmlichkeiten 41 haben werden. Die Entnahme dieser für die Laboruntersuchungen benötigten Menge an Blut 42 43 wird von Patienten im Allgemeinen ohne Symptome oder Beschwerden vertragen. Ferner wird 44 am OP-Tag eine Gewebeprobe des entfernten Tumors sowie ein kleines Stück normales 45

Bauchspeicheldrüsengewebe vom ohnehin entfernten Resektat entnommen. Falls sich der on September 28, 2021 by guest. Protected copyright. 46 Tumorbefund während der Operation wider Erwartens als nicht komplett entfernbar darstellen 47 48 sollte, z.B. weil Absiedelungen auffallen, welche in der Bildgebung vor der Operation nicht zu 49 sehen waren, dann wird eine Gewebeprobe (entweder des Primärtumors, von Lymphknoten 50 oder den Absiedelungen) entnommen. Eine derartige Gewebeprobe stellt ebenfalls ein 51 Standardvorgehen zur histologischen Sicherung des Tumors dar und wird ebenfalls im 52 53 Allgemeinen ohne relevante Beeinträchtigungen oder Beschwerden toleriert. 54 Die Gesamtdauer der Studie beträgt 24 Monate. In dieser Zeit werden zu zuvor festgelegten 55 56 Zeitpunkten (Visiten) Gesundheitsdaten von Ihnen erhoben, die für die geplanten Aussagen 57 der Studie benötigt werden. Die erste klinische Visite ist die am heutigen Tage, danach finden 58 am Operationstag, an Tag 7 nach der Operation und am Entlasstag bzw. spätestens Tag 14 59 nach der Operation Visiten statt, bei denen jeweils spezifische Daten über Ihren Verlauf 60 erhoben werden. Nach Entlassung findet eine weitere Visite an Tag 30 nach der Operation

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9 statt; zu diesem Zeitpunkt müssen Sie noch einmal in das Studienzentrum kommen. Die 10 11 weiteren Nachuntersuchungen werden mit Ihren ohnehin notwendigen Nachsorgeunter- 12 suchungen kombiniert (3, 6, 12 und 24 Monate nach der Operation). Falls Sie die weiteren 13 Nachsorgeuntersuchungen nicht an der Universitätsklinik Heidelberg durchführen lassen 14 möchten, werden Sie zu diesen Zeitpunkten von Studienpersonal kontaktiert und nach Ihrem 15 16 Befinden und Verlauf befragt. 17 Zusätzliche Medikamente (auch rezeptfreie), von denen der Prüfarzt noch nichts weiß, dürfen 18 For peer review only 19 Sie für die Zeit der Einnahme der Studienmedikation – außer bei Notfällen – nur nach 20 Rücksprache mit Ihrem Prüfarzt einnehmen. Wenn Sie von anderen Ärzten behandelt werden, 21 sollten Sie diese über Ihre Teilnahme an der klinischen Prüfung informieren. Auch Ihr Prüfarzt 22 muss informiert werden, wenn ein anderer Arzt Sie während der klinischen Prüfung behandelt. 23 24 Sie erhalten einen Studienausweis, den Sie während der Studiendauer immer mit sich führen 25 sollten. 26 27 Die Studienmedikamente sollten Sie so sicher aufbewahren, dass sie für Kinder oder andere 28 Personen, die die möglichen Risiken nicht einschätzen können, nicht erreichbar sind. Die 29 Abgabe an Dritte ist untersagt. Die Medikamente müssen bei Raumtemperatur (15-20 °C) 30 gelagert werden. 31 32 33 34 4. Welchen persönlichen Nutzen habe ich von der Teilnahme an der Studie? 35 36 Falls die Medikamente tatsächlich die erhoffte Wirkung zeigen, dann kann es sein, dass das 37

Wiederauftreten Ihrer Erkrankung verzögert oder verhindert wird. Mit Ihrer Teilnahme an dieser http://bmjopen.bmj.com/ 38 Studie unterstützen Sie die Wissenschaft dabei, neue Erkenntnisse über die Behandlung Ihrer 39 40 Erkrankung zu gewinnen, die dazu beitragen, dass man für Patienten zukünftig bessere 41 Behandlungen entwickeln kann. Nach wissenschaftlichen Erkenntnissen können auch 42 Placebos Wirkungen und Nebenwirkungen erzeugen, auch wenn diese im Allgemeinen nicht 43 so stark ausgeprägt sind. 44 45 on September 28, 2021 by guest. Protected copyright. 46 5. Welche Risiken sind mit der Teilnahme an der Studie verbunden? Welche Nebenwirkungen 47 48 gibt es? 49 50 Bekannte Nebenwirkungen von Propranolol, die in ca. 1-10% der Patienten auftreten: 51 Starker Blutdruckabfall oder eine Verringerung der Herzfrequenz. In diesem Fall muss der 52 Prüfarzt/behandelnde Arzt entscheiden, ob die Studienmedikation weiter eingenommen 53 54 werden darf oder abgesetzt werden sollte. Falls Sie bereits niedrigen Blutdruck oder eine 55 Herzerkrankung habe, dürfen Sie an der Studie nicht teilnehmen. 56 57 Das Reaktionsvermögen kann soweit verändert sein, dass die Fähigkeit zur aktiven Teilnahme 58 am Straßenverkehr, zum Bedienen von Maschinen oder zum Arbeiten ohne sicheren Halt 59 beeinträchtigt wird. Dies gilt in verstärktem Maße bei Behandlungsbeginn sowie im 60 Zusammenwirken mit Alkohol.

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9 Allgemeine Beschwerden wie Müdigkeit, Schwindelgefühl, Benommenheit, Verwirrtheit, 10 11 Kopfschmerzen, Nervosität, Schwitzen, Schlafstörungen, depressive Verstimmungen, 12 Albträume, Halluzinationen, Missempfindungen (z.B. Kribbeln), Kältegefühl an Extremitäten. 13 14 Vorübergehende Wirkungen auf den Magen-Darm-Trakt wie Übelkeit, Erbrechen, Verstopfung, 15 Durchfall oder allergische Hautreaktionen (Rötung, Juckreiz, Ausschlag) und Haarausfall. 16 17 Deutlich weniger häufig als die o.a. Nebenwirkungen werden eine Verminderung der 18 Blutplättchen oderFor kleine, peer wie Ausschlag review aussehende only Blutungen in der Haut (Purpura) 19 beobachtet, die bei einem bis höchstens 10 von 1000 Patienten (0,1 – 1%) auftreten. 20 21 22 Bekannte Nebenwirkungen von Etodolac, die in ca. 1-10% der Patienten auftreten: 23 Allgemeine Beschwerden: Schwindel – hierdurch kann die Fahrtüchtigkeit und das Bedienen 24 von Maschinen beeinträchtigt werden; Kopfschmerzen, Schlaflosigkeit, Nervosität, 25 Ängstlichkeit, Müdigkeit, Schwäche, Unwohlsein, Depression, Fieber, Frösteln. 26 27 Magen-Darm: Abdominale Schmerzen, Übelkeit, Erbrechen, Durchfall, Sodbrennen, 28 Verdauungsstörungen, Blähungen, Verstopfung. 29 30 Ohrgeräusche (Tinnitus), Ausschlag, Juckreiz, Wasseransammlungen (Ödeme) und häufiges 31 Wasserlassen. 32 33 Weniger häufige Nebenwirkungen, die in mindestens 1 von 1000 Patienten, aber weniger als 1 34 von 100 auftreten können: 35 36 Nebenwirkungen auf das Blut wie Verminderung oder Einschränkung der Funktion von 37 einzelnen oder allen Blutbestandteilen kommen (Blutplättchen, verschiedene weiße http://bmjopen.bmj.com/ 38 39 Blutkörperchen, rote Blutkörperchen). 40 Während Propranolol den Blutdruck senkt, kann Etodolac zu hohem Blutdruck, 41 42 Kreislaufkollaps oder einer Gefäßentzündung führen. 43 Nebenwirkungen auf die Haut: Verfärbungen oder fleckige Blutungen, Schwitzen, Ausschlag 44 45 mit Bläschen oder Blasen, Lichtempfindlichkeit, Überempfindlichkeitsreaktionen wie kleine on September 28, 2021 by guest. Protected copyright. 46 Blutungen, verschiedene Ausschläge, Stevens-Johnson-Syndrom, allergische Reaktionen oder 47 akuter Allergie ähnliche Reaktionen, Asthma. 48 49 Wenn Sie unter irgendwelchen Beschwerden leiden oder Veränderungen bei sich feststellen, 50 dann sollten Sie diese in Ihrem Patiententagebuch vermerken und mit dem Arzt besprechen, 51 damit dieser notwendige Gegenmaßnahmen oder Behandlungen durchführen kann. Bei 52 53 starken Beschwerden, die mit den Studienmedikamenten zusammenhängen könnten, muss 54 die Medikamenteneinnahme beendet und unverzüglich festgestellt werden, ob Placebo oder 55 Etodolac/Propranolol eingenommen wurden. 56 57 Es können auch andere seltene oder unvorhergesehene Nebenwirkungen auftreten, die 58 bislang nicht bekannt sind. 59 60

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9 Wechselwirkungen mit anderen Medikamenten: 10 11 Die Behandlung mit Propranolol und Etodolac kann zu unerwünschten Wechselwirkungen mit 12 anderen Medikamenten führen. Aus diesem Grund ist es sehr wichtig, dass Sie Ihrem Prüfarzt 13 14 mitteilen, welche Medikamente Sie aktuell einnehmen. Ebenso wichtig ist es, dass Sie im 15 Verlauf der Studie im Falle einer Erkrankung, die medikamentös behandelt werden muss, Ihren 16 behandelnden Arzt über Ihre Studienteilnahme unterrichten. 17 18 For peer review only 19 6. Welche anderen Behandlungsmöglichkeiten gibt es außerhalb der Studie? 20 21 22 Die Medikamentenkombination Etodolac und Propranolol wird in dieser Studie zusätzlich zur 23 üblichen Behandlung Ihrer Bauchspeicheldrüsenerkrankung eingesetzt. Sie ersetzt keine 24 andere Behandlung, da es außerhalb dieser Studie in der aktuellen Routine keine sonstige 25 Therapie im perioperativen Zeitraum gibt, die zum selben Zweck eingesetzt wird. 26 27 28 7. Wer darf an dieser klinischen Prüfung nicht teilnehmen? 29 30 31 Schwangere Frauen dürfen an dieser klinischen Prüfung nicht teilnehmen. Zu Beginn der 32 klinischen Prüfung müssen sich deshalb alle Frauen im gebärfähigen Alter einem 33 Schwangerschaftstest unterziehen. Davon ausgenommen sind Frauen nach den 34 Wechseljahren oder solche, die operativ sterilisiert wurden. Durch einen Schwangerschaftstest 35 36 kann jedoch eine Schwangerschaft erst einige Tage nach der Empfängnis verlässlich 37 nachgewiesen werden. http://bmjopen.bmj.com/ 38 39 Im Falle Ihrer Teilnahme an dieser klinischen Prüfung müssen Sie zuverlässige Maßnahmen 40 zur Schwangerschaftsverhütung bis mindestens 30 Tage nach Ende der Studienmedikation 41 anwenden. Diese sind der Verzicht auf Geschlechtsverkehr, Sterilität des Partners oder 42 hormonelle Verhütungsmethoden, wie z. B. die Einnahme der Anti-Baby-Pille (orale 43 44 Kontrazeptiva), empfängnisverhütende Spritzen (Dreimonatsspritze). Eine weitere Maßnahme 45 nennt sich Doppel-Barriere-Methode. Darunter versteht man die Kombination der Spirale on September 28, 2021 by guest. Protected copyright. 46 (Intrauterinpessar) oder Diaphragmas / einer Portiokappe mit Spermizid zusammen mit der 47 Nutzung eines Kondoms durch den Partner. Der Grund dafür ist, dass das Medikament 48 49 Etodolac zu Schädigungen des Ungeborenen und zu Fehlgeburten führen kann. 50 Von Propranolol ist bekannt, dass der Wirkstoff die Plazenta passiert und im Nabelschnurblut 51 52 etwas höhere Konzentrationen als im Blut der Schwangeren erreicht. Zwar gibt es keine 53 ausreichenden Studien zur Anwendung des Medikamentes bei schwangeren Frauen, dennoch 54 können mögliche Komplikationen während der Schwangerschaft und für das Neugeborene 55 nicht ausgeschlossen werden. 56 57 Sollten Sie während der klinischen Prüfung schwanger werden oder den Verdacht haben, dass 58 Sie schwanger geworden sind, müssen Sie umgehend den Prüfarzt informieren. 59 60 Auch stillende Frauen dürfen an dieser klinischen Prüfung nicht teilnehmen, da Etodolac mit der Muttermilch in den Körper des Kindes gelangen und zu seiner Schädigung führen könnte.

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9 Wenn bei Ihnen eine Allergie gegen eines der Medikamente vorliegt, dürfen Sie nicht an dieser 10 11 klinischen Studie teilnehmen. Weiterhin gibt es einige Ein- und Ausschlusskriterien, die von 12 Ihrem Prüfarzt vor Studieneinschluss überprüft werden. 13 14 15 8. Entstehen für mich Kosten durch die Teilnahme an der klinischen Prüfung? 16 17 Durch Ihre Teilnahme an dieser klinischen Prüfung entstehen für Sie keine zusätzlichen 18 For peer review only 19 Kosten. 20 21 22 9. Bin ich während der klinischen Prüfung versichert? 23 24 Bei der klinischen Prüfung eines Arzneimittels sind alle Studienteilnehmer gemäß dem 25 Arzneimittelgesetz versichert. Der Umfang des Versicherungsschutzes ergibt sich aus den 26 Versicherungsunterlagen, die Sie zusammen mit dieser Information und der von Ihnen 27 28 datierten und unterschriebenen Einwilligung zur Studienteilnahme ausgehändigt 29 bekommen. Eine Wegeunfallversicherung ist darin nicht enthalten. 30 31 Wenn Sie vermuten, dass durch die Teilnahme an der klinischen Prüfung Ihre Gesundheit 32 geschädigt oder bestehende Leiden verstärkt wurden, müssen Sie dies unverzüglich dem 33 Versicherer 34 HDI Global SE 35 Am Schönenkamp 45, 40599 Düsseldorf 36 Tel. 0211 748 2240, Fax 0211 748 2470 37 Versicherungsnummer: 57 010310 03018 http://bmjopen.bmj.com/ 38 39 direkt anzeigen, gegebenenfalls mit Unterstützung durch Ihren Prüfarzt, um Ihren 40 Versicherungsschutz nicht zu gefährden. Sofern Ihr Prüfarzt Sie dabei unterstützt, erhalten 41 42 Sie eine Kopie der Meldung. Umgekehrt informieren Sie bitte zusätzlich Ihren Prüfarzt, falls 43 Sie Ihre Anzeige direkt an den Versicherer richten. Bei der Aufklärung der Ursache oder des 44 Umfangs eines Schadens müssen Sie mitwirken und alles unternehmen, um den Schaden 45 abzuwenden oder zu mindern. on September 28, 2021 by guest. Protected copyright. 46 47 Während der Zeit der Medikamenteneinnahme dürfen Sie sich einer anderen medizinischen 48 Behandlung – außer in Notfällen – nur nach vorheriger Rücksprache mit dem Prüfarzt 49 50 unterziehen. Von einer erfolgten Notfallbehandlung müssen Sie den Prüfarzt unverzüglich 51 unterrichten. 52 53 54 10. Werden mir neue Erkenntnisse während der klinischen Prüfung mitgeteilt? 55 56 Sie werden über neue Erkenntnisse, die in Bezug auf diese klinische Prüfung bekannt werden 57 und die für Ihre Bereitschaft zur weiteren Teilnahme wesentlich sein können, informiert. Auf 58 59 dieser Basis können Sie dann Ihre Entscheidung zur weiteren Teilnahme an dieser klinischen 60 Prüfung überdenken.

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3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 7 UniversitätsKlinikum Heidelberg 8 9 10 11. Wer entscheidet, ob ich aus der klinischen Prüfung ausscheide? 11 12 Sie können jederzeit, auch ohne Angabe von Gründen, Ihre Teilnahme beenden, ohne dass 13 Ihnen dadurch irgendwelche Nachteile bei Ihrer medizinischen Behandlung entstehen. Unter 14 15 gewissen Umständen ist es aber auch möglich, dass der Prüfarzt entscheidet, Ihre Teilnahme 16 an der klinischen Prüfung vorzeitig zu beenden, ohne dass Sie auf die Entscheidung Einfluss 17 haben. Die Gründe hierfür können z. B. sein: 18 ° Ihre weitere TeilnahmeFor an peer der klinischen review Prüfung ist ärztlich only nicht mehr vertretbar. 19 20 ° Die gesamte klinische Prüfung wird abgebrochen. 21 22 Sofern Sie sich dazu entschließen, vorzeitig aus der klinischen Prüfung auszuscheiden, oder 23 Ihre Teilnahme aus einem anderen der genannten Gründe vorzeitig beendet wird, ist es für Ihre 24 eigene Sicherheit wichtig, dass Sie sich einer empfohlenen abschließenden 25 Kontrolluntersuchung unterziehen. Der Prüfarzt wird mit Ihnen besprechen, wie und wo Ihre 26 27 weitere Behandlung stattfindet. 28 29 30 12. Was geschieht mit meinen Daten? 31 32 Die ärztliche Schweigepflicht und datenschutzrechtliche Bestimmungen werden eingehal- 33 ten. Während der Studie werden medizinische Befunde und persönliche Informationen 34 von Ihnen erhoben und in der Prüfstelle in Ihrer persönlichen Akte niedergeschrieben oder 35 elektronisch gespeichert. Die für die Studie wichtigen Daten werden zusätzlich in pseudo- 36 1 37 nymisierter Form gespeichert und am Universitätsklinikum (Koordinierungszentrum für http://bmjopen.bmj.com/ 38 Klinische Studien (KKS), Im Neuenheimer Feld 130.3 , 69120 Heidelberg) ausgewertet. Die 39 Studienleitung wird alle angemessenen Schritte unternehmen, um den Schutz Ihrer Daten 40 gemäß den Datenschutzstandards der Europäischen Union zu gewährleisten. Die Daten 41 sind gegen unbefugten Zugriff gesichert. Eine Entschlüsselung erfolgt nur, wenn diese 42 medizinisch notwendig ist oder bei Rücktritt von der Studie zum Zweck der Datenvernich- 43 44 tung. Sobald es nach dem Forschungs- oder Statistikzweck möglich ist und keine sonsti- 45 gen Pflichten zur Aufbewahrung personenbezogener Daten bestehen (vgl. Punkt 3 der Da- on September 28, 2021 by guest. Protected copyright. 46 tenschutzerklärung in der folgenden Einwilligungserklärung), werden die personenbezo- 47 genen Daten anonymisiert2. Die während der Studie erhobenen Daten werden nach Studi- 48 enabschluss 10 Jahre aufbewahrt. Die Daten werden ausschließlich zu Zwecken dieser 49 Studie verwendet. 50 51 Sie haben das Recht, vom Verantwortlichen (s.u.) Auskunft über die von Ihnen gespeicher- 52 ten personenbezogenen Daten zu verlangen. Ebenfalls können Sie die Berichtigung unzu- 53 treffender Daten oder die Einschränkung deren Verarbeitung verlangen; die Löschung der 54 55 56 1„Pseudonymisierung“ ist die Verarbeitung personenbezogener Daten in einer Weise, dass die personenbezo- 57 genen Daten ohne Hinzuziehung zusätzlicher Informationen („Schlüssel“) nicht mehr einer spezifischen be- 58 troffenen Person zugeordnet werden können. Diese zusätzlichen Informationen werden dabei gesondert auf- 59 bewahrt und unterliegen technischen und organisatorischen Maßnahmen, die gewährleisten, dass die perso- 60 nenbezogenen Daten nicht einer identifizierten oder identifizierbaren natürlichen Person zugewiesen werden. 2„Anonymisierung“ ist das Verändern personenbezogener Daten in der Weise, dass die betroffene Person nicht mehr oder nur mit einem unverhältnismäßig großen Kosten- oder Zeitaufwand identifiziert werden kann.

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9 Daten können Sie verlangen, sofern deren Aufbewahrung nicht gesetzlich vorgeschrieben 10 11 ist (vgl. Punkt 3 der Datenschutzerklärung in der folgenden Einwilligungserklärung). 12 Der Verantwortliche für die studienbedingte Erhebung personenbezogener Daten ist: 13 14 Prof. Dr. med. Markus K. Diener 15 Tel. 06221/56-6986 16 E-Mail: [email protected] 17 18 Die Details zur VerarbeitungFor peer der personenbezogenen review Datenonly finden Sie in der Datenschut- 19 zerklärung im Rahmen der nachfolgenden Einwilligungserklärung. Bei Anliegen zur Daten- 20 verarbeitung und zur Einhaltung der datenschutzrechtlichen Anforderungen können Sie sich 21 22 an folgenden Datenschutzbeauftragten der Einrichtung wenden: 23 Der Datenschutzbeauftragte des Universitätsklinikums Heidelberg 24 25 Im Neuenheimer Feld 130.3, 69120 Heidelberg 26 [email protected] 27 Im Falle einer rechtswidrigen Datenverarbeitung haben Sie das Recht, sich bei folgender 28 29 Aufsichtsbehörde zu beschweren: 30 31 Der Landesbeauftragte für den Datenschutz 32 und die Informationsfreiheit Baden-Württemberg 33 Postfach 10 29 32, 70025 Stuttgart 34 Königstraße 10a, 70173 Stuttgart 35 Tel.: 0711/61 55 41 – 0 36 Fax: 0711/61 55 41 – 15 37 http://bmjopen.bmj.com/ 38 E-Mail: [email protected] 39 Internet: http://www.baden-wuerttemberg.datenschutz.de 40 Für die Zwecke der Studie ist es nützlich, auch Daten aus Ihrer Krankenakte bei Ihrem Hausarzt 41 42 einzubeziehen. Wir möchten Sie bitten, einer Weitergabe dieser Daten an die Studienleitung 43 zuzustimmen und Ihren Hausarzt insoweit von der Schweigepflicht zu entbinden. 44 45 on September 28, 2021 by guest. Protected copyright. 46 13. Was geschieht mit meinen Blut- und Gewebeproben? 47 48 49 Ihre Blutproben werden im Labor des Universitätsklinikums Heidelberg analysiert, um fest- 50 zustellen, welchen Einfluss die Medikamenteneinnahme auf die Entzündungs-, und Stressre- 51 aktionen in Ihrem Körper und auf die Abwehrzellen hat. Auch beim Gewebe des Tumors und 52 der Bauchspeicheldrüse wird untersucht, ob Veränderungen durch die Einnahme der Studi- 53 54 enmedikation hervorgerufen wurden und welche dies sind. 55 Die Proben werden ebenso wie alle anderen in der Studie erhobenen Daten mit einem Code 56 57 pseudonymisiert, so dass man sie mit der Medikamenteneinnahme und dem Verlauf Ihrer 58 Erkrankung in Beziehung bringen kann, ohne dass Ihr Name bekannt wird. 59 60 Die Aufbewahrung der Proben erfolgt im Labor des Universitätsklinikums Heidelberg. Sie werden für mindestens 10 Jahre nach Abschluss der Prüfung aufbewahrt und können mög-

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9 licherweise auch für weitere Fragen im Zusammenhang mit den Prüfpräparaten oder Ihrer 10 11 Grunderkrankung verwendet werden, wenn sich im Laufe der Zeit neue wissenschaftliche 12 Erkenntnisse oder Möglichkeiten ergeben. Wenn Sie Ihre Teilnahme an der klinischen Prü- 13 fung vorzeitig beenden möchten, können Sie entscheiden, ob Ihre Proben vernichtet werden 14 sollen oder in pseudonymisierter Form weiter verwendet werden dürfen. Sie können jeder- 15 16 zeit nach Ende Ihrer Teilnahme die Vernichtung der entnommenen Proben verlangen. 17 18 For peer review only 19 14. Wissenschaftliche und kommerzielle Nutzung der Forschungsergebnisse 20 21 Die Ergebnisse dieser Studie sollen veröffentlicht werden, z.B. in wissenschaftlichen Zeit- 22 schriften und auf Konferenzen. Diese Veröffentlichungen werden keinerlei persönliche Da- 23 24 ten enthalten, die Rückschlüsse auf Ihre Person ermöglichen. Zudem ist es möglich, dass 25 die Forschungsergebnisse kommerziell genutzt, z.B. patentiert werden. An einem möglichen 26 kommerziellen Nutzen werden Sie nicht beteiligt. 27 28 Die Studie ist im Deutschen Register Klinischer Studien unter der Nummer DRKS00014054 29 registriert (www.drks.de). Publikationen der Studienergebnisse werden im Register erfasst. 30 Sie finden im Register Informationen über den allgemeinen Ausgang und die allgemeinen 31 32 Ergebnisse der Studie. Bei weiteren Fragen zu dem Ausgang der Studie können Sie sich an 33 den Leiter der Studie, Prof. Dr. Markus Diener (Kontaktdaten vgl. Abschnitt 12), wenden. 34 35 36 15. An wen wende ich mich bei weiteren Fragen? 37 http://bmjopen.bmj.com/ 38 Beratungsgespräche an der Prüfstelle 39 40 Sie haben stets die Gelegenheit zu weiteren Beratungsgesprächen mit dem Prüfarzt, der Sie 41 aufgeklärt hat oder über unser Kontakttelefon im KSC (s. S. 1). 42 43 Kontaktstelle 44 45 Es existiert außerdem eine Kontaktstelle bei der zuständigen Bundesoberbehörde. Teilnehmer on September 28, 2021 by guest. Protected copyright. 46 an klinischen Prüfungen, ihre gesetzlichen Vertreter oder Bevollmächtigten können sich an 47 diese Kontaktstelle wenden: 48 49 Bundesinstitut für Arzneimittel und Medizinprodukte 50 Fachgebiet Klinische Prüfung / Inspektionen 51 Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn 52 53 Telefon: 0228 / 207-4318 Fax: 0228 / 207-4355, 54 E-mail: [email protected] 55 56 Bitte geben Sie bei schriftlichen Anfragen im Betreff „Klinische Prüfung / Inspektion“ sowie die 57 58 EUDRACT-Nr. 2018-000415-25 der Studie an. 59 60

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9 10 11 PROSPER-Studie 12 Randomisierte Phase II–Studie zur perioperativen Off-Label Behandlung mit Propranolol und 13 Etodolac im Rahmen von Bauchspeicheldrüseneingriffen 14 15 16 Einwilligungserklärung 17 18 For peer review only 19 20 21 22 ...... 23 Name des Patienten in Druckbuchstaben 24 25 26 27 geb. am ...... Teilnehmer-Nr...... 28 29 30 Ich bin in einem persönlichen Gespräch durch den Prüfarzt 31 32 33 34 ...... 35 Name der Ärztin/des Arztes 36 37 http://bmjopen.bmj.com/ 38 ausführlich und verständlich über die Prüfmedikamente und die Vergleichstherapie sowie 39 über Wesen, Bedeutung, Risiken und Tragweite der klinischen Prüfung aufgeklärt worden. Ich 40 habe darüber hinaus den Text der Patienteninformation sowie die hier nachfolgend 41 42 abgedruckte Datenschutzerklärung gelesen und verstanden. Ich hatte die Gelegenheit, mit 43 dem Prüfarzt über die Durchführung der klinischen Prüfung zu sprechen. Alle meine Fragen 44 wurden zufrieden stellend beantwortet. 45 on September 28, 2021 by guest. Protected copyright. 46 47 Möglichkeit zur Dokumentation zusätzlicher Fragen seitens des Patienten oder sonstiger 48 Aspekte des Aufklärungsgesprächs: 49 50 51 52 53 54 55 56 57 58 59 60

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9 10 11 Ich hatte ausreichend Zeit, mich zu entscheiden. 12 13 Mir ist bekannt, dass meine Teilnahme an der Studie freiwillig ist und ich diese jederzeit 14 mündlich oder schriftlich und ohne Angabe von Gründen zurückziehen und die Vernichtung 15 16 meiner Blut-/Gewebeproben fordern kann, ohne dass mir daraus Nachteile für meine 17 medizinische Behandlung entstehen. 18 For peer review only 19 20 Datenschutz: 21 22 Mir ist bekannt, dass bei dieser klinischen Prüfung personenbezogene Daten, insbesondere 23 medizinische Befunde über mich erhoben, gespeichert und ausgewertet werden sollen. Die 24 25 Verarbeitung der Daten erfolgt nach gesetzlichen Bestimmungen und setzt vor der Teilnahme 26 an der klinischen Prüfung gemäß Art. 6 Abs. 1 lit. A der Datenschutz-Grundverordnung 27 folgende freiwillig abgegebene Einwilligungserklärung voraus. (Ohne die nachfolgende 28 Einwilligung kann ich nicht an der klinischen Prüfung teilnehmen). 29 30 1. Ich wurde darüber aufgeklärt und stimme freiwillig zu, dass meine in der Studie erhobenen 31 Daten, insbesondere Angaben über meine Gesundheit, zu den in der Informationsschrift 32 33 beschriebenen Zwecken in pseudonymisierter Form in Papierform sowie auf 34 elektronischen Datenträgern aufgezeichnet, ausgewertet und ggf. auch in 35 pseudonymisierter Form an folgende Empfänger weitergegeben werden: 36 37 a) an das Universitätsklinikum Heidelberg (Prüfstelle: Klinik für Allgemein-, Viszeral- http://bmjopen.bmj.com/ 38 und Transplantationschirurgie des Universitätsklinikums Heidelberg, Im Neuenheimer 39 Feld 110 und Koordinierungszentrum für Klinische Studien (KKS), Im Neuenheimer Feld 40 41 130.3 , 69120 Heidelberg). 42 b) im Falle eines Antrags auf Zulassung: an den Antragsteller und die für die Zulassung 43 44 zuständige Behörde: das Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), 45 c) im Falle unerwünschter Ereignisse: an das Universitätsklinikum Heidelberg, den on September 28, 2021 by guest. Protected copyright. 46 47 Studienleiter, an die Abteilung Pharmakovigilanz des KKS-Heidelberg (Koordinierungs- 48 zentrum für Klinische Studien), die zuständige Ethikkommission und die zuständige 49 Bundesoberbehörde, das Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) 50 sowie von dieser an die Europäische Arzneimittel-Datenbank. 51 52 2. Außerdem erkläre ich mich damit einverstanden, dass autorisierte und zur Verschwie- 53 genheit verpflichtete Beauftragte des Universitätsklinikums Heidelberg, z.B. ein Monitor 54 55 des Studienzentrums der Deutschen Gesellschaft für Chirurgie sowie die zuständigen 56 Überwachungsbehörden in meine beim Prüfarzt vorhandenen personen-bezogenen Daten, 57 insbesondere meine Gesundheitsdaten, Einsicht nehmen, soweit dies für die Überprüfung 58 der ordnungsgemäßen Durchführung der Studie notwendig ist. Für diese Maßnahme 59 60 entbinde ich den Prüfarzt von der ärztlichen Schweigepflicht.

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3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 6 7 UniversitätsKlinikum Heidelberg 8 9 10 3. Ich bin darüber aufgeklärt worden, dass ich jederzeit die Teilnahme an der klinischen 11 Prüfung beenden kann. Die Einwilligung zur Erhebung und Verarbeitung meiner 12 personenbezogenen Daten, insbesondere der Angaben über meine Gesundheit, ist jedoch 13 14 unwiderruflich Ich weiß, dass im Falle eines Widerrufs zur Teilnahme an der klinischen 15 Prüfung die bis zu diesem Zeitpunkt gespeicherten Daten weiterhin verwendet werden 16 dürfen, soweit dies erforderlich ist, um 17 18 a) Wirkungen desFor zu prüfenden peer Arzneimittels review festzustellen, only 19 20 b) sicherzustellen, dass meine schutzwürdigen Interessen nicht beeinträchtigt werden, 21 c) der Pflicht zur Vorlage vollständiger Zulassungsunterlagen zu genügen. 22 23 4. Ich erkläre mich damit einverstanden, dass meine Daten und Proben nach Beendigung 24 oder Abbruch der Prüfung mindestens zehn Jahre aufbewahrt werden, wie es die 25 26 Vorschriften über die klinische Prüfung von Arzneimitteln bestimmen. Danach werden 27 meine personenbezogenen Daten gelöscht, soweit nicht gesetzliche oder satzungsmäßige 28 Aufbewahrungsfristen entgegenstehen. 29 30 5. Ich bin über folgende gesetzliche Regelung informiert: Falls ich meine Einwilligung, an der 31 Studie teilzunehmen, widerrufe, müssen alle Stellen, die meine personen-bezogenen 32 Daten, insbesondere Gesundheitsdaten, gespeichert haben, unverzüglich prüfen, 33 34 inwieweit die gespeicherten Daten für die in Nr. 3 a) bis c) genannten Zwecke noch 35 erforderlich sind. Nicht mehr benötigte Daten sind unverzüglich zu löschen. 36 37 6. Ich bin damit einverstanden, dass mein Hausarzt http://bmjopen.bmj.com/ 38 39 40 ...... 41 42 Name 43 44 über meine Teilnahme an der klinischen Prüfung informiert wird (falls nicht gewünscht, 45 bitte streichen) und gegebenenfalls für die Studie wichtige Gesundheitsdaten (z.B. aus on September 28, 2021 by guest. Protected copyright. 46 47 Nachuntersuchungen) zur Verfügung stellt. Diesbezüglich entbinde ich meinen Hausarzt 48 von der ärztlichen Schweigepflicht. 49 50 51 52 53 54 55 56 57 58 59 60

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10 11 Ich erkläre mich bereit, an der oben genannten klinischen Prüfung freiwillig teilzunehmen. 12 13 Ein Exemplar der Patienteninformation und –einwilligung sowie die Versicherungsbedin- 14 gungen habe ich erhalten. Ein Exemplar verbleibt im Prüfzentrum. 15 16 17 18 For peer review only 19 20 21 22 ...... 23 24 Name des Patienten in Druckbuchstaben 25 26 27 28 29 30 31 ...... 32 Datum der Einwilligung Unterschrift des Patienten 33 34 35 36 37 Ich habe das Aufklärungsgespräch geführt und die Einwilligung des Patienten eingeholt. http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 ...... on September 28, 2021 by guest. Protected copyright. 46 Name des Prüfarztes/der Prüfärztin in Druckbuchstaben 47 48 49 50 51 52

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Article Type: Protocol

Date Submitted by the 26-Aug-2020 Author:

Complete List of Authors: Hüttner, Felix; University of Heidelberg, Department of General, Visceral and Transplantation Surgery; University of Heidelberg, The Study Center of the German Surgical Society (SDGC) Rooman, Ilse; The Anticancer Fund; Vrije Universiteit Brussel, Laboratory of Medical and Molecular Oncology Bouche, Gauthier; The Anticancer Fund Knebel, Phillip; UniversitatsKlinikum Heidelberg, Department of General, Visceral and Transplantation Surgery Hüsing, Johannes; Heidelberg University, Coordination Center for Clinical Trials Mihaljevic, A; UniversitätsKlinikum Heidelberg, Thilo, Hackert; Heidelberg University, Department of General, Visceral and Transplantation Surgery http://bmjopen.bmj.com/ Strobel, Oliver ; Heidelberg University, Department of General, Visceral and Transplantation Surgery Buchler, Markus W.; UniversitätsKlinikum Heidelberg, Department of General, Visceral and Transplantation Surgery Diener, M. K.; Heidelberg University, Department of General, Visceral and Transplantation Surgery

Primary Subject Oncology Heading: on September 28, 2021 by guest. Protected copyright. Secondary Subject Heading: Surgery

Gastrointestinal tumours < ONCOLOGY, Adult oncology < ONCOLOGY, Keywords: Pancreatic surgery < SURGERY

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1 2 3 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Introduction 6 Pancreatic cancer is the fourth leading cause of cancer-related death in developed countries. Despite 7 8 advances in systemic chemotherapy, the mainstay of curative therapy for non-metastatic disease is 9 surgical resection. However, the perioperative period is characterized by stress and inflammatory 10 11 reactions that can contribute to metastatic spread and disease recurrence. Catecholamines and 12 13 prostaglandins play a crucial role in these reactions. Therefore, a drug repurposing of betablockers and 14 cyclooxygenase inhibitors seems reasonable to attenuate tumor-associated inflammation by inhibiting 15 16 psychological, surgical and inflammatory stress responses. This may cause a relevant antitumorigenic 17 and antimetastatic effect during the perioperative period, a window for cancer-directed therapy that is 18 For peer review only 19 currently largely unexploited. 20 21 22 Methods and analysis 23 24 This is a prospective, single-center, two-arm randomized, patient and observer blinded, placebo- 25 controlled, phase-2 trial evaluating safety and feasibility of combined perioperative treatment with 26 27 propranolol and etodolac in adult patients with non-metastatic cancer of the pancreatic head undergoing 28 elective pancreatoduodenectomy. 100 patients fulfilling the eligibility criteria will be randomized to 29 30 perioperative treatment for 25 days perioperatively with a combination of propranolol and etodolac or 31 32 placebo. Primary outcome of interest will be safety in terms of serious adverse events and reactions 33 within 3 months. Furthermore, adherence to trial medication will be assessed as feasibility outcomes. 34 35 Preliminary efficacy data will be evaluated for the purpose of power calculation for a potential 36 subsequent phase-3 trial. The clinical trial is accompanied by a translational study investigating the 37 http://bmjopen.bmj.com/ 38 mechanisms of action of the combined therapy on a molecular basis. 39 40 41 Ethics and dissemination 42 43 The PROSPER-trial has been approved by the German Federal Institute for Drugs and Medical Devices 44 (reference number 4042875) and the Ethics Committee of the Medical Faculty of the University of 45 on September 28, 2021 by guest. Protected copyright. 46 Heidelberg (reference number AFmo-385/2018). The final trial results will be published in a peer 47 reviewed journal and will be presented at appropriate national and international conferences. 48 49 50 51 Trial registration number 52 DRKS00014054; EudraCT number: 2018-000415-25 53 54 55 56 57 58 59 60

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1 2 3 Strengths and limitations of this study BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 - This is the first clinical trial assessing a combined treatment with a betablocker (propranolol) 6 and a cyclooxygenase inhibitor (etodolac) in the perioperative period surrounding partial 7 8 pancreatoduodenectomy for cancer of the pancreatic head. 9 10 - Strengths of this study are its randomized, double-blind, placebo-controlled design and its 11 transparent design with the clear definitions of endpoints. 12 13 - Potential limitation include the rather small sample size leading to a limited power and the 14 broad exclusion criteria, which may limit generalizability of the data, because of the selected 15 16 trial population. 17 - If the trial treatment proves to be safe, the perioperative period may be used as a window for 18 For peer review only 19 cancer-directed therapy and the results will form the basis for a subsequent phase III trial. 20 21 22 INTRODUCTION 23 24 More than 450,000 new cases of pancreatic cancer are diagnosed worldwide per year.1 In contrast to 25 many other cancers, its incidence and mortality have been rising during the last decades and the 26 27 prognosis is devastating with a 5-year overall survival of < 10%.2 3 Despite substantial advancements in 28 29 systemic chemotherapy during recent years, the mainstay of curatively intended treatment remains 30 surgical resection. However, only a small proportion of patients present with potentially resectable 31 4 32 disease (primary resectable or borderline resectable) at diagnosis. With modern multimodal treatment 33 strategies consisting of resection and adjuvant chemotherapy, a median overall survival of 54 months 34 35 can be reached, but disease-free survival at three years is still < 50% in these patients.5 36 For patients with potentially resectable tumors, the perioperative time period, which spans an 37 http://bmjopen.bmj.com/ 38 interval from the timepoint of diagnosis until the actual start of adjuvant chemotherapy, 39 6 40 represents a window of opportunity for perioperative therapy aimed to reduce recurrence. The 41 psychological stress and the emotions around diagnosis, surgery and upcoming chemotherapy 42 43 are accompanied by increased release of catecholamines exerting their effects on tumor cells 44 and stromal cells that express adrenergic receptors. On one hand, catecholamine release is 45 on September 28, 2021 by guest. Protected copyright. 46 an adaptive reaction to cope with stressful situations by modulating the immune response and 47 48 mobilizing metabolic reserves. On the other hand, these stress responses are also pro- 49 tumorigenic with pleiotropic effects on the primary tumor, the tumor microenvironment, 50 7 51 malignant cells in the circulation and on pre-existing micrometastases. Interestingly, the 52 effects of catecholamines may be counteracted by adrenergic receptor antagonists (beta- 53 54 blockers), often prescribed for hypertension or cardiac disease. 55 Surgically induced inflammation and the subsequent release of prostaglandins are additional 56 57 mediators of tumorigenic and pro-metastatic effects in the perioperative period despite their 58 8 59 role in tissue repair and regeneration. Prostaglandins facilitate tumor cell survival, proliferation 60 and invasion and also counteract immunosurveillance.9-11 Prostaglandins promote

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1 2 3 angiogenesis and epithelial-mesenchymal transition and they lead to a release of pro-survival BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 7 8 5 and growth factors for malignant cells. In addition, prostaglandins promote microvascular 6 barrier dysfunction, endothelial hyperpermeability and lymphatic dilation, which can facilitate 7 8 lymphatic and distant metastases.12-14 Prostaglandin synthesis from arachidonic acid involves 9 the cyclooxygenases (COX), of which COX-2 is the inducible form that is particularly active 10 11 during inflammation by generating prostaglandin E2 (PGE-2). COX are druggable targets and 12 13 the above-mentioned effects could be counteracted by selective COX-2 inhibitors. 14 The term ‘drug repurposing’ describes an approach trying to repurpose well-characterised drugs for a 15 16 previously untested indication. This emerging strategy is of particular interest for oncologic purposes.15 17 16 In terms of drug repurposing a combination therapy of propranolol, a non-selective beta-blocker, and 18 For peer review only 19 etodolac, a semiselective COX-2 inhibitor, in the perioperative setting of pancreatic cancer resection 20 may result in attenuation of tumor-associated inflammation and stress responses..17 By these 21 22 mechanisms, it may cause a relevant antitumorigenic and antimetastatic effect during the perioperative 23 24 period, which is a currently largely unexploited window for therapies aiming to influence these stress 25 and inflammatory responses. Promising results of this ‘drug repurposing’ have been shown in both, 26 27 preclinical and early clinical trials for other solid cancer entities. In an experimental liver metastasis 28 mouse model of colorectal cancer, treatment with propranolol and etodolac reduced hepatic metastases 29 30 in the context of surgery.18 Furthermore, in a phase-2 randomized controlled trial on colorectal cancer, 31 32 the treatment was well tolerated and showed favorable results regarding early biomarkers of metastatic 33 potential, but also three-year recurrence rates.19 34 35 The primary objective of this pilot trial, will be to assess the safety of the combination therapy with 36 propranolol and etodolac in the perioperative setting of pancreatic cancer surgery. Beyond safety, 37 http://bmjopen.bmj.com/ 38 feasibility will be analyzed, since the two predominant factors for curative treatment (surgery and 39 adjuvant chemotherapy) must not be affected by the above-mentioned drug administration. If the trial 40 41 treatment proves to be safe and feasible, the survival data derived from the current trial will form the 42 43 basis for a subsequent confirmatory phase-3 trial assessing its efficacy. 44 45 on September 28, 2021 by guest. Protected copyright. 46 METHODS AND ANALYSIS 47 Study design 48 49 The PROSPER-trial is a two-arm randomized, patient and observer blinded, placebo-controlled, phase-2 50 51 trial. The primary objective is to evaluate safety and feasibility of perioperative propranolol and etodolac 52 treatment in patients with resectable cancer of the pancreatic head planned for elective 53 54 pancreatoduodenectomy. Additionally, early parameters of efficacy will be assessed by analyzing 55 survival of the patients and by an ancillary translational study investigating the mechanisms of action of 56 57 the combined therapy on a molecular basis. The trial will be performed in a single-center setting at the 58 Department of General, Visceral and Transplantation Surgery of the University Hospital Heidelberg, 59 60 Germany, a center of excellence for pancreatic surgery with high volume in oncologic pancreatic

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3 BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 Feasibility endpoints 6 Feasibility will be assessed by the evaluation of adherence to study medication intake. The rationale for 7 8 this endpoint is that there are some factors in the perioperative period, which might preclude patients 9 from taking the intended medication (e.g. delayed gastric emptying/gastroparesis, nausea/vomiting, 10 11 intolerable bradycardia under propranolol, etc.). This would hamper a wide-spread implementation into 12 13 treatment protocols. Adherence to study medication will thus provide more insight into the feasibility 14 of implementing treatment with propranolol and etodolac into perioperative treatment plans. Adherence 15 16 to trial medication will be documented in a medication diary. Every patient will be asked to document 17 his drug intake or any impediments. Furthermore, all used or unused blister packs will need to be turned 18 For peer review only 19 in to the trial center by the patients. Opened packages with left-over investigational medicinal product 20 (IMPs) will be accounted for at the trial center. The percentage of the finally taken medication from the 21 22 planned medication will be documented in the electronic case report form (eCRF). 23 24 Furthermore, completion of adjuvant chemotherapy will be evaluated as another measure of feasibility. 25 This endpoint provides further insight into the practicality of implementing the trial intervention into 26 27 modern routine treatment schedules. 28 29 30 Efficacy endpoints 31 32 Overall and disease-free survival will be assessed as oncologic long-term variables. Survival is the 33 ultimate goal of any cancer directed therapy. Apart from overall survival, disease-free survival has been 34 35 proven to be a reliable parameter in phase II/III clinical trials. 36 Furthermore, rates of local and distant recurrence will be assessed as another efficacy outcome. All of 37 http://bmjopen.bmj.com/ 38 these preliminary efficacy endpoints will be evaluated for the purpose of a power calculation for a 39 potential subsequent phase-3 trial. 40 41 42 43 Biological endpoints 44 Biological endpoints/Biomarkers will be measured at different timepoints of study conduct as described 45 on September 28, 2021 by guest. Protected copyright. 46 above. The following parameters will be assessed: 47 Blood samples: 48 49 1. Routine laboratory biomarkers: differential blood count, c-reactive protein (CRP), 50 51 albumin, carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) 52 2. Translational study biomarkers: phenotyping of circulating immune cells (FACS), 53 54 cytokine multiplex, PGE-2 levels, circulating tumor cells, RNA sequencing in periphery blood 55 cells (leukocytes) 56 57 Tissue samples (translational part of the study): 58 1. Biomarkers associated with COX-2 inhibition: COX-2, PGE-2, interleukin 6 (IL-6) 59 60 expression

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29 Day of surgery POD 14/ discharge Day before surgery 30 10-28daysafter V1 31 Eligibility criteria X X 32 Baseline data, 33 X 34 demographics 35 Randomization X 36 Previous 37 X

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1 2 3 periphery blood cells (leukocytes; POD 3). The tumor tissue, which is sampled at surgery, will be BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 investigated by tissue cultures (organoids and pluripotent stem cells). Furthermore, COX-2 expression, 6 PGE-2 levels and immune cell infiltration will be investigated and RNA sequencing of bulk tissue or of 7 8 sorted tumor and stromal cells will be performed. 9 10 11 Data handling and monitoring 12 13 An investigator or a designated representative will enter all protocol-required data into the eCRF. All 14 entries in the eCRF must be verifiable by source documents. Data entries will undergo an automatic 15 16 online check for plausibility and consistency. Upon completion of the eCRF, the investigator has to 17 confirm the accuracy of all data by signing sections online in the eCRF. 18 For peer review only 19 On site visits will be done by the monitor at regular intervals to ensure compliance with the trial protocol, 20 ICH good clinical practice (GCP) guidelines and legal aspects. The monitor must be given access to all 21 22 trial relevant documents by the investigator. He will review the entries into the eCRF for completeness 23 24 and correctness and verify the entries on the basis of the source documents. The responsible monitor 25 and the data manager can generate special questions (queries) that will be sent back to the responsible 26 27 investigator. The investigator or a designated representative will have to answer them all in a timely 28 manner. 29 30 Data management and monitoring activities will be performed according to the current standard 31 32 operating procedures of the Coordination Center for Clinical Trials (KKS) or the Study Center of the 33 German Surgical Society (SDGC) respectively. 34 35 36 Statistical analysis 37 http://bmjopen.bmj.com/ 38 The main safety, feasibility and efficacy variables will be analyzed with generalized linear models or 39 Cox regression models. Parameter estimates from these models will be reported with 95 percent profile 40 41 likelihood-based confidence intervals. All other variables will be tabulated by treatment group using 42 number of missing and non-missing values, the quartiles, mean and standard deviation. 43 44 All subjects who have ever been randomized to study treatment will form the full analysis set for efficacy 45 on September 28, 2021 by guest. Protected copyright. 46 purposes. All patients will be analyzed according to the treatment group they have been randomized to, 47 regardless of the treatment they actually received (intention-to-treat). A restricted full analysis set will 48 49 be formed by the set of subjects undergoing surgical resection of the pancreas. Patients not undergoing 50 surgery at all or patients, who did not take at least 50% of their preoperative trial medication will be 51 52 replaced. The per-protocol set will comprise all patients receiving at least 75% per cent of study 53 54 medication at the appropriate time points. The safety set will contain all patients ever receiving study 55 medication and will assign patients to treatment group according to the treatment they actually received. 56 57 Analysis with respect to the primary safety endpoints will be conducted using the safety set. Feasibility 58 will be compared using the full analysis set, whereas analysis on efficacy will be conducted using the 59 60 restricted full analysis set. A sensitivity analysis for efficacy will be per-formed for the per protocol set.

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1 2 3 Author contributions BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 FJH, IR, GB, PK, JH, ALM, TH, OS and MKD designed the study protocol. All authors contributed to 6 the study design. FJH, IR, GB, OS, MWB and MKD initiated this clinical study. FJH and MKD wrote 7 8 the paper. All authors approved the final version of this manuscript. All authors agreed to be 9 accountable for all aspects of the work, and ensure that any questions related to the accuracy or 10 11 integrity of any part of the work will be appropriately investigated and resolved. 12 13 14 Funding statement 15 16 This clinical trial is financed with donations of Het Anti-Kankerfonds (Anticancer Fund), a Belgian- 17 based private foundation (grant number: A56). No commercial stakeholder was involved in the 18 For peer review only 19 planning or conduct of this trial. 20 21 22 Disclaimer 23 24 The funding source of the trial does not have a role in data collection, data analysis, or interpretation 25 of the trial results. 26 27 28 Competing interests statement 29 30 None declared. 31 32 33 Trial status 34 35 The first patient was included on January 11th 2019. Recruitment is currently ongoing. 36 37 http://bmjopen.bmj.com/ 38 Acknowledgements 39 We thank Inga Rossion (SDGC) and Liese Vandeborne (Anticancer Fund) for their ongoing support 40 41 regarding this trial in various aspects. Additionally, we appreciate the work of all contributors from the 42 43 Anticancer Fund, the KKS, the SDGC as well as from the clinical study center of the Department of the 44 General, Visceral and Transplantation Surgery of the University Heidelberg. Furthermore, we want to 45 on September 28, 2021 by guest. Protected copyright. 46 acknowledge the honorary work of the members of the DSMB: Richard Jackson, Cancer Research UK 47 Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, United Kingdom; Paul Karanicolas 48 49 (Sunnybrooke Health Sciences Centre, Toronto, Ontario, Canada); Erica Sloan (Institute of 50 51 Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 52 53 54 55 56 57 58 59 60

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27 http://bmjopen.bmj.com/ Visit 3 OP Day OP Day 28 29 30 31 Visit 4 - 6 POD 1/ 3/ 5 POD 1/ 3/ 5 32 33 34 Visit 7 POD 7 POD 7

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1 2 3 Appendix 1: List of contraindications to propranolol and/or etodolac: BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 • Known allergy or hypersensitivity to propranolol and/or etodolac and/or any other ingredient of 6 the used brands 7 • History or evidence of significant cardiac disease: congestive or severe heart failure; New 8 York Heart Association class ≥ 2; active coronary artery disease; unstable angina, cardiac 9 arrhythmias requiring anti-arrhythmic therapy, uncontrolled hypertension, patients with recent 10 (less than 6 months) myocardial infarction or coronary re-vascularization; cardiogenic shock; 11 sick sinus syndrome; sinoatrial block; acidosis 12 • Hypotension at the time of screening (i.e., systolic blood pressure < 100 mmHg. Diastolic 13 blood pressure < 60 mmHg) 14 • Symptomatic bradycardia or resting heart rate < 50 bpm at time of screening 15 • Bronchial hyperresponsiveness, including active chronic asthma 16 • Active peptic ulcer disease or gastrointestinal bleeding 17 • Decompensated diabetes mellitus (repeated measurements of glucose > 300 mg/dl despite 18 usual medicalFor treatment, peer (keto-) acidosis, review exsiccosis due only to decompensated diabetes) 19 • Chronic inflammatory bowel disease (M. Crohn or Ulcerative colitis) 20 • Severe peripheral vascular disease 21 • Concurrent use of monoaminooxidase inhibitor (excluding monoaminooxidase-B inhibitor) 22 • Intravenous application of calcium channel blockers (non-dihydropyridine) and other 23 antiarrhythmic agents 24 • Severe thrombocytopenia 25 • Sensitivity to aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) in terms of 26 asthma, urticarial or acute rhinitis 27 • Chronic use of any beta-adrenergic blocker within the last 3 months 28 • Chronic use of any cyclooxygenase (COX) inhibitor within the last 3 months 29 30 • Participation in another interventional trial 31 • Pharmaceutical preparations with which major interactions can be expected by propranolol 32 and/or etodolac in patients’ long-term therapy* 33 • Diseases or findings that may have a significant effect on the target variables and which may 34 therefore mask or inhibit the therapeutic effect under investigation 35 • Persons with any kind of dependency on the investigator or employed by the sponsor or 36 investigator 37 • Persons held in an institution by legal or official order; legally incapacitated patients http://bmjopen.bmj.com/ 38 • Persons with understanding/language problems or inability to comply with study and/or follow- 39 up procedures 40 • Any condition which could result in an undue risk for the patient and/or influence out-come 41 measures in the opinion of the investigator 42 43 *see Appendix 2 for possible interactions 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Appendix 2: Possible major interactions with patient’s concomitant medication BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 5 A) Etodolac: 6 Severity: Major 7 Risk rating: Avoid combination 8 • NSAIDs and selective COX-2 inhibitors may enhance the adverse/toxic effect of Etodolac. 9 • Etodolac (as a photosensitizing agent) may enhance the photosensitizing effect of 10 Aminolevulinic Acid (5-ALA). Avoid administration of other photosensitizing agents within 24 11 hours before or 24 hours after orally administered 5-ALA. As 5-ALA is administered for 12 visualization of malignant tissue in glioma patient, it is unlikely that study participant 13 experience this kind of interaction. 14 • Etodolac may enhance the anticoagulant effect of Urokinase. 15 16 Severity: Major 17 Risk rating: Consider therapy modification 18 • Etodolac mayFor enhance peerthe adverse/toxic review effect of Apixaban, only Rivaroxaban, Dabigatran 19 Etexilate, Edoxaban. Specifically, the risk of bleeding may be increased. If combined, monitor 20 patients extra closely for signs and symptoms of bleeding with any concurrent use, and 21 counsel patients about the increased risk of bleeding and the need to promptly report any 22 signs or symptoms of possible bleeding. 23 • Monitor for decreased serum concentrations/therapeutic effects Etodolac if coadministered 24 with bile acid sequestrants (Cholestyramine Resin). Separating the administration of doses by 25 2 or more hours may reduce (but not eliminate) the risk of interaction. 26 • Etodolac may enhance the nephrotoxic effect of Cyclosporine. Monitor for evidence of 27 nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects 28 (e.g. hypertension) during concomitant therapy. 29 • Etodolac may increase the serum concentration of Lithium. Consider reducing the dosage of 30 lithium upon initiation of Etodolac. Monitor for increased therapeutic/toxic effects of lithium if 31 Etodolac is initiated/dose increased, or decreased effects if Etodolac is discontinued/dose 32 decreased. 33 • Etodolac may increase the serum concentration of Methotrexate. If methotrexate and Etodolac 34 are to be used concomitantly, monitor patients for evidence of hematologic toxicity (frequent 35 complete blood count), nephrotoxicity (frequent serum creatinine), and hepatotoxicity (liver 36 function tests). 37 • Etodolac may enhance the adverse/toxic effect of Salicylates (excluding low dose acetyl- http://bmjopen.bmj.com/ 38 salicylic acid, e.g. aspirin 100 mg/day). 39 • Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Etodolac. 40 Etodolac may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. To 41 minimize the risk of bleeding associated with this combination, consider using alternative 42 analgesics, when appropriate, and/or addition of a gastroprotective agent, such as a proton 43 pump inhibitor for the time that combined therapy is necessary. 44 • Sodium Phosphates may enhance the nephrotoxic effect of Etodolac. Specifically, the risk of 45 acute phosphate nephropathy may be enhanced. This interaction has only been demonstrated on September 28, 2021 by guest. Protected copyright. 46 with large oral sodium phosphate doses used for bowel preparation (typically greater than 20 47 g). 48 • Etodolac may enhance the nephrotoxic effect of Tenofovir Products. Avoid concurrent use of 49 tenofovir with high-dose of Etodolac when possible due to a potential risk for acute renal 50 failure. This risk has been most clearly shown with the NSAID diclofenac, but some data 51 suggest that other NSAIDs may also be capable of interacting with tenofovir. 52 • Etodolac may enhance the anticoagulant effect of Vitamin K Antagonists (Acenocoumarol, 53 Phenindione, Warfarin). Monitor for increased signs and symptoms of bleeding. 54

55 B) Propranolol: 56 Severity: Major 57 Risk rating: Avoid combination 58 • Propranolol may diminish the bronchodilatory effect of Beta-2-Agonists (Bambuterol, 59 Fenoterol, Formoterol, Indacaterol, Levosalbutamol, Olodaterol, Orciprenalin, Salbutamol, 60 Salmeterol, Terbutaline, Vilanterol).

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1 2 3 • Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Avoid BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 concurrent use of ceritinib with propranolol when possible. If such use cannot be avoided, 5 monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure 6 and heart rate during therapy. Adjustment of ceritinib therapy (i.e., dose reduction and/or 7 temporary discontinuation) may be necessary for symptomatic bradycardia. 8 • Propranolol may enhance the adverse/toxic effect of Methacholine. Methacholine 9 administration is contraindicated in patients receiving any beta-blocker. 10 • Rivastigmine may enhance the bradycardic effect of propranolol. Due to the risk of additive 11 bradycardic effects, including syncope, the concomitant use of rivastigmine and beta-blockers 12 is not recommended. 13 14 Severity: Major 15 Risk rating: Consider therapy modification 16 • Abiraterone Acetate may increase the serum concentration of propranolol (as a CYP2D6 17 substrate). When concurrent use is not avoidable, monitor patients closely for signs/symptoms 18 of propranololFor toxicity. peer review only 19 • CYP2D6 inhibitors: Fluoxetine, Paroxetine, Quinidine, Tipranavir may decrease the 20 metabolism of propranolol. Consider an alternative for one of the interacting drugs in order to 21 avoid toxicity of propranolol. Some combinations are specifically contraindicated by 22 manufacturers. Suggested dosage adjustments are also offered by some manufacturers. 23 Please review applicable package inserts. Monitor for increased effects of propranolol if a 24 cytochrome P (CYP) inhibitor is initiated/dose increased, and decreased effects if a CYP 25 inhibitor is discontinued/dose decreased. 26 • Dronedarone may enhance the bradycardic effect of propranolol and increase the serum 27 concentration of propranolol. 28 • Fluvoxamine (as a CYP1A2 inhibitor) may increase effects of propranolol is initiated/dose 29 increased, and decrease effects if fluvoxamine is discontinued/dose decreased. 30 • Propranolol may enhance the vasopressor effect of direct-acting Alpha-/Beta-Agonists 31 (Dopamine, Ephedrine (Nasal), Ephedrine (Systemic), Epinephrine (Nasal), Epinephrine (Oral 32 Inhalation), Epinephrine (Systemic), Isometheptene, Levonordefrin, Metaraminol, 33 Norepinephrine). Epinephrine used as a local anesthetic for dental procedures will not likely 34 cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta- 35 Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished 36 by Beta-Blockers. Monitor for increases in pressor effects of alpha-/beta-agonists if used in 37 patients receiving propranolol. Beta-1-selective (i.e., “cardioselective”) agents may confer a http://bmjopen.bmj.com/ 38 more limited risk if used in low enough doses to allow them to retain their selectivity. Infiltrating 39 larger volumes of local anesthetics for other surgical procedures (e.g., more than 0.06mg 40 epinephrine) may cause clinically-relevant problems. Patients with allergies that require 41 carrying and periodically using subcutaneous epinephrine (e.g. bee sting kits) should probably 42 avoid the use of propranolol. 43 • Alpha-2-Agonists (Brimonidine (Ophthalmic), Clonidine, Dexmedetomidine, Guanfacine, 44 Lofexidine, Methyldopa, Moxonidine, Rilmenidine, Tizanidine, Excep-tion: Apraclonidine) may 45 enhance the atrio-ventricular-blocking (AV-block) effect of propranolol. Sinus node dysfunction on September 28, 2021 by guest. Protected copyright. 46 may also be enhanced. Propranolol may enhance the re-bound hypertensive effect of Alpha- 47 2-Agonists. This effect can occur when the Alpha-2-Agonist is abruptly withdrawn. 48 • Propranolol may enhance the hypotensive effect of Amifostine. Amifostine should not be 49 administered when propranolol is concomitantly used. 50 • Propranolol may enhance the vasoconstricting effect of Ergot Derivatives (Bromocriptine, 51 Cabergoline, Dihydroergotamine, Ergoloid Mesylates, Ergonovine, Ergotamine, 52 Methylergonovine, Pergolide, Exception: Nicergoline). Consider alternatives whenever 53 possible in order to avoid this combination. If concurrent use cannot be avoided, monitor 54 patients closely for evidence of excessive peripheral vasoconstriction. 55 • Beta-Blockers may enhance the bradycardic effect of Fingolimod. Avoid the concomitant use 56 of fingolimod and beta-blockers if possible. If co-administration is necessary, patients should 57 have overnight continuous electrocardiogram monitoring conducted after the first dose of 58 fingolimod. Closely monitor patients for the development of bradycardia and other serious 59 arrhythmias. 60 • Obinutuzumab may enhance the hypotensive effect of propranolol. In order to minimize the risk of excessive hypotension during or immediately after obinutuzumab infusion, clinicians

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1 2 3 should consider temporarily withholding propranolol beginning 12 hours prior to infusion and BMJ Open: first published as 10.1136/bmjopen-2020-040406 on 30 September 2020. Downloaded from 4 continuing until 1 hour after infusion and until the patient's blood pressure is stable. 5 • Panobinostat may increase the serum concentration of propranolol. Avoid concurrent use of 6 propranolol when possible. If such a combination cannot be avoided, monitor patients closely 7 for evidence of propranolol toxicity. 8 • Propranolol may increase the serum concentration of Rizatriptan. Rizatriptan dose should be 9 reduced to 5mg in patients who are also being treated with propranolol. Monitor clinical 10 response to rizatriptan closely with use of this combination. 11 • Propranolol may diminish the bronchodilatory effect of Theophylline Derivatives 12 (Acebrophylline, Aminophylline, Dyphylline, Theophylline). Consider avoiding the concomitant 13 use of propranolol and theophylline derivatives. If concomitant use cannot be avoided, monitor 14 for symptoms of reduced theophylline efficacy. 15 • Propranolol may increase the serum concentration of Tizanidine. Avoid the use of tizanidine 16 with propranolol when possible. If combined use cannot be avoided, initiate tizanidine at an 17 adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor 18 for increased Foreffects of peertizanidine, including review adverse reactions only (e.g. hypotension, bradycardia, 19 drowsiness). 20 • Vemurafenib may increase the serum concentration of propranolol. Consider alternatives to 21 such combinations whenever possible. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 28, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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