Effects of Peripherally Acting µ-opioid Receptor Antagonists on Acute Pancreatitis - An Investigator-initiated, Randomized, Placebo-controlled, Double-blind Clinical Trial
Phase: PHASE2
Conditions: Acute Pancreatitis
Sponsor: Asbjørn Mohr Drewes

 
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Effects of peripherally acting µ-opioid receptor 
antagonists on acute pancreatitis 
An investigator-initiated, randomized, placebo-controlled, double-blind 
clinical trial 
 
Aalborg University Hospital, Odense University Hospital,  
Hvidovre University Hospital, and Bispebjerg University Hospital 
 
 

 
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Table of contents 
Protocol signature page .............................................................................................................................................. 5 
1. Glossary .................................................................................................................................................................. 6 
2. Project participants and study centers .................................................................................................................... 8 
3. Funding ..................................................................................................................................................................12 
4. Roles and responsibilities ......................................................................................................................................12 
5. Time schedule ........................................................................................................................................................13 
6.  Introduction ..........................................................................................................................................................14 
6.1. Background and rationale ..................................................................................................................................... 14 
6.1.1. Study medication ........................................................................................................................................... 16 
6.2. Hypothesis ............................................................................................................................................................. 16 
6.3. Trial design ............................................................................................................................................................ 17 
7. Methods: participants, interventions, and outcomes ............................................................................................17 
7.1. Study setting .......................................................................................................................................................... 17 
7.2. Eligibility criteria .................................................................................................................................................... 17 
7.2.1. Inclusion criteria ............................................................................................................................................. 17 
7.2.2. Exclusion criteria ............................................................................................................................................ 18 
7.3. Interventions .......................................................................................................................................................... 18 
7.3.1. Methylnaltrexone dosage and treatment duration ....................................................................................... 18 
7.3.2. Discontinuation or withdrawal from the study .............................................................................................. 18 
7.3.3. Adherence ...................................................................................................................................................... 19 
7.3.4. Concomitant medication and care ................................................................................................................. 19 
7.4. Outcomes............................................................................................................................................................... 20 
7.4.1. Primary endpoint ........................................................................................................................................... 20 
7.4.2. Secondary endpoints ..................................................................................................................................... 20 
7.5. Participant timeline ............................................................................................................................................... 20 

 
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7.5.1. Study days ...................................................................................................................................................... 20 
7.6. Sample size ............................................................................................................................................................ 22 
7.7. Recruitment ........................................................................................................................................................... 22 
7.8. Information about the study ................................................................................................................................. 22 
8. Methods: Allocation of interventions ....................................................................................................................23 
8.1. Allocation ............................................................................................................................................................... 23 
8.2. Blinding .................................................................................................................................................................. 23 
9. Methods: Data collection, management, and analysis ...........................................................................................24 
9.1. Data collection methods ........................................................................................................................................ 24 
9.1.1. Pancreatitis Activity Scoring System .............................................................................................................. 24 
9.1.2. Clinical outcome and health resource utilization........................................................................................... 25 
9.1.3. Questionnaires ............................................................................................................................................... 26 
9.1.4. Biochemistry .................................................................................................................................................. 26 
9.1.5. Imaging ........................................................................................................................................................... 26 
9.1.6. PEG 400/4000 test ......................................................................................................................................... 27 
9.2. Data management ................................................................................................................................................ 27 
9.2.1. Case report forms .......................................................................................................................................... 28 
9.2.2. Source data identification and protection ..................................................................................................... 28 
9.3. Statistical methods ................................................................................................................................................ 29 
9.3.1. Criteria for the termination of the trial .......................................................................................................... 29 
9.3.2. Missing data ................................................................................................................................................... 29 
9.3.3. Deviations from the original statistical plan .................................................................................................. 29 
10. Methods: monitoring ...........................................................................................................................................29 
10.1. GCP monitor ........................................................................................................................................................ 29 
10.2. Assessment of safety and harms ......................................................................................................................... 30 
10.2.1. Adverse event and adverse reaction ........................................................................................................... 30 
10.2.2. Serious adverse event or serious adverse reaction ..................................................................................... 31 
10.2.3. Safety follow-up procedure ......................................................................................................................... 32 
10.3. Quality control and quality assurance ................................................................................................................. 32 
11. Ethics and dissemination .....................................................................................................................................34 

 
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11.1. Risks related to the experimental procedures ..................................................................................................... 34 
11.2. Risks related to study medication ........................................................................................................................ 34 
11.3. Patient insurance ................................................................................................................................................. 35 
11.4. Consent and confidentiality ................................................................................................................................. 35 
11.5. Declaration of interests ....................................................................................................................................... 35 
11.6. Access to data...................................................................................................................................................... 35 
11.7. Dissemination policy ............................................................................................................................................ 36 
Reference list .............................................................................................................................................................37 
 
 
 
 
 
 
 
 

 
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Protocol signature page 
 
Investigator’s statement: 
I have read and understand the foregoing protocol entitled “Effects of peripherally acting µ-opioid receptor 
antagonists on acute pancreatitis” protocol no. PAMORA_2020 and agree to conduct the study in compliance 
with Good Clinical Practice (CPMP/ICH/135/95), designated Standard Operating Procedures, the Danish 
Medicines Agency, the Research Ethics Committee in Denmark, and within the principles of the Declaration 
of Helsinki (amended by the 52nd General Assembly, Edinburgh, Scotland, October 2000, clarified by the 
General Assembly in Washington 2002, Tokyo 2004, Seoul 2008, and Fortaleza 2013 as outlined herein). 
 
Asbjørn Mohr Drewes  
Professor, Chief Consultant 
Principal investigator and sponsor 
Principal investigator/sponsor’s title 
05-08-2020 
 
Date 
Principal investigator/sponsor’s signature 
 
 
 
 
 
 
 

 
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1. Glossary 
OPAC 
 
Odense pancreas center 
ICH 
 
International conference on harmonization 
AP  
 
Acute pancreatitis 
SIRS 
 
Systemic inflammatory response syndrome 
PAMORAs 
 
Peripherally acting μ-opioid receptor antagonists 
SIBO  
 
Small intestinal bacterial overgrowth 
eGFR 
 
Estimated glomerular filtration rate  
CRF 
 
Case report form 
PASS 
 
Pancreatitis activity scoring system 
HbA1c  
 
HemoglobinA1c  
CRP 
 
C-reactive protein 
IL 
 
Interleukin 
TNF-α 
 
Tumor necrosis factor alpha 
CD163 
 
Cluster of differentiation 163 
PaO2 
 
Partial pressure of oxygen in arterial blood  
GSRS 
 
Gastrointestinal symptom rating scale  
SOP 
 
Standard operating procedure 
GCP 
 
Good clinical practice 
AE  
 
Adverse event  
AR 
 
Adverse reaction  
SAE 
 
Serious adverse event  
SAR 
 
Serious adverse reaction  
SUSAR 
 
Suspected unexpected serious adverse reaction 

 
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mSV 
 
Millisievert 
 
 
 
 
 
 

 
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2. Project participants and study centers 
Sponsor and principal investigator:  
Asbjørn Mohr Drewes, Professor, MD, DMSc, PhD   
Centre for pancreatic diseases and Mech-Sense 
Department of Gastroenterology & Hepatology  
Aalborg University Hospital  
9000 Aalborg, Denmark  
Telephone: +45 97 66 35 62  
E-mail: amd@rn.dk 
 
Principal investigator Odense: 
Michael Bau Mortensen, Professor, MD, DMSc, PhD 
Odense Pancreas Center (OPAC), HPB Section, Department of Surgery 
Odense University Hospital  
5000 Odense, Denmark  
Telephone: +45 65 41 18 57 
E-mail: michael.bau.mortensen@rsyd.dk 
 
Principal investigator Hvidovre: 
Srdan Novovic, MD, Consultant, PhD 
Gastrounit  
Hvidovre University Hospital  
2650 Hvidovre, Denmark  
Telephone: +45 38 62 13 50 
E-mail: srdan.novovic@regionh.dk 
 
 
 

 
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Principal investigator Bispebjerg: 
Liv Bjerre Juul Nielsen, MD, Consultant 
Digestive Disease Center K 
Bispebjerg University Hospital  
2400 København NV, Denmark  
Telephone: +45 38 63 50 00 
E-mail: liv.bjerre.juul.nielsen@regionh.dk 
 
Delegates: 
Søren Schou Olesen, Associate professor, MD, PhD   
Centre for pancreatic diseases and Mech-Sense 
Department of Gastroenterology & Hepatology  
Aalborg University Hospital  
9000 Aalborg, Denmark  
Telephone: +45 97 66 35 10 
E-mail: soso@rn.dk 
 
Cecilie Siggaard Knoph, MD, PhD-student 
Centre for pancreatic diseases and Mech-Sense 
Department of Gastroenterology and Hepatology 
Aalborg University Hospital 
9000 Aalborg, Denmark  
Telephone: +45 97 66 35 20 
Email: c.siggaard@rn.dk 
 
Camilla Ann Fjelsted, MSc, PhD-student 
Centre for pancreatic diseases and Mech-Sense 
Department of Gastroenterology and Hepatology 
Aalborg University Hospital 
9000 Aalborg, Denmark  

 
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Telephone: +45 97 66 35 20 
Email: c.fjelsted@rn.dk  
 
Jens Brøndum Frøkjær, Professor, MD, PhD 
Centre for pancreatic diseases and Mech-Sense 
Department of Radiology 
Aalborg University Hospital 
9000 Aalborg, Denmark  
Email: jebf@rn.dk 
Telephone: +: +45 97 66 51 05  
 
Primary study center:  
Centre for pancreatic diseases 
Department of Gastroenterology & Hepatology  
Aalborg University Hospital  
9000 Aalborg, Denmark  
 
Other study centers: 
Odense Pancreas Center (OPAC), HPB Section, Department of Surgery 
Odense University Hospital  
5000 Odense, Denmark  
 
Gastrounit  
Hvidovre University Hospital  
2650 Hvidovre, Denmark  
 
Digestive Disease Center K 
Bispebjerg University Hospital  
2400 København NV, Denmark  
 

 
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Monitor:  
The GCP-unit at Aalborg and Aarhus University Hospitals  
Palle Juul-Jensens Boulevard 82 
8200 Aarhus N, Denmark  
Telephone: +45 78 41 39 50  
 
 

 
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3. Funding  
The study was conceived and initiated by Professor Asbjørn Mohr Drewes, Department of Gastroenterology 
& Hepatology, Aalborg University Hospital. It is economically supported by a free grant of 7.3 MIO DKK by 
the Novo Nordisk Foundation. This grant will be used to cover expenses related to equipment, medication 
and salary for study personnel. The Novo Nordisk Foundation does not have any specific rights related to 
publication of the results, and positive as well as negative and/or inconclusive results will be published in 
scientific journals. All data will be publicly available to anybody incl. the Novo Nordisk Foundation after 
publication. Various funds will be applied for, to cover any additional financial expenses. Alternatively, Mech-
Sense, Aalborg University Hospital will cover the remaining expenses. The grant from the Novo Nordisk 
Foundation as well as potential grants from other funds are deposited in a project account at the Hospital, 
which principal investigator Asbjørn Mohr Drewes is responsible for. Any excess amount will be refunded 
after the study has been concluded. The involved researchers conduct the trial of general scientific interest 
without personal financial gain and none of the researchers involved in this study have economical interest 
in the Novo Nordisk Foundation or other financial supporters of this study. 
 
4. Roles and responsibilities  
The present clinical study will be conducted in compliance with this protocol, the guidelines of the World 
Medical Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, October 2013), the 
guidelines of International Conference on Harmonization (ICH) GCP (CPMP/ICH/135/95), and designated 
Standard Operating Procedures.  
The study will be conducted at four referral centers for pancreatitis in Denmark, located at Aalborg, Odense, 
Bispebjerg and Hvidovre University Hospitals. Aalborg University Hospital will take leadership as main 
sponsor for the clinical trial and has the overall responsibility for the quality of the study. Professor Asbjørn 
Mohr Drewes who is specialist in gastroenterology, will be principal investigator and overall study 
coordinator. He will lead the study together with Associate Professor Søren Schou Olesen and other 
researchers at Centre for Pancreatic Diseases and Mech-Sense at Aalborg University Hospital. These will assist 
in design, write the protocol, handle all procedures with the regulatory authorities and be responsible for 
data management, data analysis as well as publications. They have a long track record on research in clinical 
and experimental pain research, pancreatitis, opioids, opioid antagonists, and imaging as well as a large 
network and major experience with leadership of multicenter studies.  

 
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Professor Jens Brøndum Frøkjær at the Department of Radiology, Aalborg University Hospital, will supervise 
the analysis of all cross-sectional imaging studies together with senior researcher Donghua Liao. The imaging 
research group at Department of Radiology is an integrated part of Centre for Pancreatic Diseases and the 
interdisciplinary research group Mech-Sense. 
Researchers at Hvidovre and Bispebjerg Hospitals will undertake the analysis of blood and urine samples. 
They have major experience in these analyses and have previously undertaken several studies in patients 
with acute pancreatitis (AP). 
Cecilie Siggaard Knoph, PhD-student at Centre for Pancreatic Diseases, Aalborg University Hospital will be 
responsible for managing and overseeing the study. This will be supported by PhD-student Camilla Ann 
Fjelsted, Mech-Sense. A Ph.D. student at Department of Radiology, Aalborg University Hospital (not yet 
appointed) will manage the advanced imaging analysis. 
 
5. Time schedule  
The study is expected to be initiated (first subject included) in December 2020 and concluded (last subject, 
last visit) by December 2023. A detailed overview is given in the diagram below. 
 
2020 
2021-2022 
2023 
Submitting protocol 
 
 
 
 
Conducting studies 
 
 
 
Data analysis 
 
 
 
Writing and submitting articles 
 
 
 
 
 

 
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6.  Introduction  
6.1. Background and rationale 
Acute pancreatitis (AP) has an annual incidence rate of approximately 35 pr. 100.000 person years in 
Denmark and has become one of the most frequent gastrointestinal discharge diagnoses (1). AP is 
associated with an overall complication rate of about 20%, and despite improved treatment the mortality is 
still near 3%. Unfortunately, no targeted pharmacologic treatment exists, to effectively alter the disease 
course, and the initial management of AP is currently based on supportive therapy with intravenous fluid 
resuscitation and analgesics. In the later stages, treatment is directed against complications such as mono- 
or multiorgan failure and infections, especially infected pancreatic necrosis (2). 
The early phase of AP is characterised by a localized pancreatic inflammatory process, which can progress 
to a systemic inflammatory response syndrome (SIRS), which may be associated with multiorgan 
dysfunction - and failure (3). In turn, a compensatory anti-inflammatory response, whereby the 
inflammation becomes controlled, counterbalances the inflammatory process. However, in some cases an 
inadequate control of this counterbalance may lead to further organ dysfunction, immune paresis and late 
complications - in particular infections.  
Pain is the cardinal symptom of AP and induces release of endogenous opioids, which is further potentiated 
by exogenous administered opioids used for pain management (4). The increased opioid exposure leads to 
a number of harmful effects on the gastrointestinal organs and the immune system (see figure 1). This may 
further promote the inflammatory response and worsen the course of the disease (5). 
 

 
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Figure 1: The effects of opioids on the gastrointestinal organs and the immune system 
 
About 20% of patients with AP will develop recurrent acute pancreatitis (RAP). The etiology of this entity 
can in most cases be related to continuation of toxic exposure (e.g. alcohol and/or smoking) or occult 
biliary stones, that have been overlooked or inadequately treated during the index attack of AP. However, 
the etiology of approximately 10-30 % of RAP cases, remains unexplained despite a thorough diagnostic 
work up (6). Currently no treatment is available for these patients and many patients will continue to suffer 
from repeated attacks of pancreatitis. A large proportion will ultimately progress to chronic pancreatitis 
with loss of exocrine and endocrine pancreatic function, chronic abdominal pain, and an increased risk for 
developing pancreatic cancer (6) with great cost for both the individual patient and society.   
Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed for the treatment of 
opioid induced bowel dysfunction (7). This specific medication group may also have beneficial effects in 
patients with AP and RAP but has never been investigated for this indication. Hence, PAMORAs have been 
shown to potentiate immune responses (8) and increase survival in cancer patients partly due to 
counteracting the harmful effects of opioids on inflammation (9). Opioid administration induces paralysis of 
the small intestines by decreased and dyscoordination of gut motility, which may promote bacterial 
overgrowth (10). Opioids also seem to augment intestinal permeability due to damage of the tight junctions 
between mucosa cells (11). Together with small intestinal bacterial overgrowth (SIBO), translocation of 

 
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bacteria from the leaky gut to the peripancreatic tissues and the systemic circulation may be fatal in 
patients with AP. PAMORAs may ameliorate this by counteracting the above-mentioned effects of opioids 
on the intestines. As the medication also increases intestinal and pancreatic fluid production and has a 
relaxing effect on the sphincter of Oddi, the administration of PAMORAs are expected to enhance flow in 
the pancreatic duct system (10) resulting in increased washout of pathogenic substances during attacks of 
AP. Also, under normal circumstances, the tone in sphincter of Oddi and pancreatic secretion is partly 
controlled by endogenous opioids, and therefore prophylactic treatment with PAMORAs in patients with 
RAP may further support flow in the pancreatic duct system.  
6.1.1. Study medication  
In this study, the effects of PAMORA on disease development and progression in patients with AP will be 
investigated. Patients with AP will be administered Methylnaltrexone (Relistor®) intravenously. This 
medication is defined as the investigational product. Relistor® is approved and sold on the Danish marked 
for treatment of opioid-induced constipation. This PAMORA have not previously been investigated in 
patients with pancreatitis. The dose regimes for this study will be according to label. Please see the 
Summary of Product Characteristics for further details. For detailed description of possible side effects, see 
section 11.2. We have previously shown, in patients with opioid-induced obstipation and healthy subjects, 
that opioid antagonism incl. PAMORA treatment increases gut motility, relaxes gastrointestinal sphincters, 
increases the intestinal water content and improves the immune response, without affecting analgesia 
(10,12–15). The affinity of PAMORAs to the µ-opioid receptors is much stronger than opioid analgesics. 
Therefore, they as antagonists have the potential to counteract the harmful effects of opioids on the gut 
mucosa, bacterial translocation and inflammation despite the high levels of exogenous opioids present in 
patients with pancreatitis. PAMORAs do not cross the blood-brain barrier and consequently do not 
interfere with analgesia or other central effects of opioids (12).  
We hypothesize that treatment with the PAMORA methylnaltrexone will antagonize the harmful effects of 
opioids without reducing analgesia in patients with AP and hence reduce disease severity and improve 
clinical outcomes. If successful, this sub-study will for the first time document the effects of a targeted 
pharmacotherapy in AP with the potential benefit of improved patient outcomes. 
6.2. Hypothesis 
In patients admitted with AP, 5 days treatment with intravenous methylnaltrexone will reduce the disease 
severity compared to placebo.  

 
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6.3. Trial design 
This study is an investigator-initiated, double-blind, placebo-controlled, parallel-group of fixed 
methylnaltrexone dose conducted at four referral centers for pancreatitis in Denmark. A group of 90 patients 
with AP will be prospectively included and randomized to receive intravenous methylnaltrexone or matching 
placebo in a 1:1 ratio. Patients will be treated for 5 days during hospital admission.   
7. Methods: participants, interventions, and outcomes  
7.1. Study setting  
The study will be conducted at four referral centers for pancreatitis in Denmark, located at Aalborg, Odense, 
Bispebjerg, and Hvidovre University Hospitals. These centers have comprehensive experience in diagnosing, 
treating, and conducting research on patients with pancreatitis.  
 
7.2. Eligibility criteria  
7.2.1. Inclusion criteria  
• 
Signed informed consent before any study specific procedures 
• 
Able to read and understand Danish 
• 
Male or female age between 18 and 85 years 
• 
The researcher believes that the participant understands what the study entails, is capable of 
following instructions, can attend when needed, and is expected to complete the study  
• 
The investigator will ensure that fertile female participants have a negative pregnancy test before 
treatment initiation and use contraception during the study period. The following methods of 
contraception, if properly used, are generally considered reliable: oral contraceptives, patch 
contraceptives, injection contraceptives, vaginal contraceptive ring, intrauterine device, surgical 
sterilization (bilateral tubal ligation), vasectomized partner, double barrier (condom and pessary), or 
sexual abstinence. Methods of contraception will be documented in the source documents 
• 
Within the current hospital admission and prior to inclusion, the patient must fulfill at least two of 
the following criteria to establish a diagnosis of AP (according to the revised Atlanta criteria (20)): i) 
abdominal pain consistent with AP (acute onset of a persistent, severe, epigastric pain often radiating 

 
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to the back); ii) serum amylase activity at least three times greater than the upper limit of normal; 
and iii) characteristic findings of AP on diagnostic imaging 
• 
Predicted moderate or severe AP based on the fulfillment of 2 or more SIRS criteria within the last 
24 hours prior to inclusion (see figure 2)  
7.2.2. Exclusion criteria  
• 
Definitive chronic pancreatitis according to the M-ANNHEIM criteria (21) - 
• 
Known allergy towards study medication  
• 
Known or suspected major obstruction or perforation of the intestines  
• 
Toxic megacolon  
• 
Known or suspected abdominal cancer (incl. intestine, pancreas and the biliary tree) 
• 
Pre-existing renal insufficiency (defined as habitual estimated glomerular filtration rate (eGFR) below 
45 ml/min/1,73m2)  
• 
End-stage renal impairment requiring dialysis prior to inclusion 
• 
Severe pre-existing comorbidities (assessed by investigator upon inclusion) 
• 
Severe non-pancreaticobiliary infections or sepsis caused by non-pancreaticobiliary disease  
• 
Child-Pugh class B or C liver cirrhosis  
• 
Females that are currently lactating  
7.3. Interventions 
7.3.1. Methylnaltrexone dosage and treatment duration  
To ensure standardization of the protocol, patients with AP will be treated with methylnaltrexone or placebo 
intravenously for the first 5 days of admission and assessments of endpoints will be done at fixed time points 
during this period. The dosage will be weight adjusted. Thus, 0.15 mg/kg methylnaltrexone or a 
corresponding volume of matching placebo (Ringer`s lactate) will be dissolved in 1000 mL Ringer`s lactate 
solution and given as a continues infusion over 24 hours using an infusion pump. In accordance with the 
summary of product characteristics for methylnaltrexone, a 50 % dose reduction will be made for patients 
with an eGFR below 30 ml/min/1,73m2. the continuous infusion of study medication will be started no later 
than 24 hours after preparation. This will be ensured by keeping detailed record on the time of preparation 

 
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as well as time of infusion start. As methylnaltrexone is sensitive to light, the solution will be kept protected 
from light from the time of preparation until the time of infusion start. Two persons trained in the protocol 
and delegated to do so, will prepare the solution of study medication together. This will be done with one 
person assisting virtually in exceptional cases.   
7.3.2. Discontinuation or withdrawal from the study  
If the treatment-responsible doctor should at any point during the study asses that the patient suffers from 
end-stage renal impairment requiring dialysis, the treatment with methylnaltrexone will be discontinued.  
Furthermore, a participant should be withdrawn from trial, if at any time:   
• 
It is the wish of the participant for any reason 
• 
The investigator judges it necessary due to medical reasons 
If a participant is withdrawn from the trial, the investigator should always ensure that:  
• 
Case report form (CRF) end of trial pages should be completed for withdrawn participants  
• 
Any serious adverse events still ongoing after ended trial will be followed until the event has been 
resolved or the investigator assesses them as chronic or stable  
7.3.3. Adherence  
Patients with AP will be admitted during study participation. Thus, medication or placebo will be 
administered at fixed time points by medical professionals and subsequently registered within the patient’s 
medical records as well as in the CRF. 
7.3.4. Concomitant medication and care  
Patients participating in the study will receive supportive treatment according to the IAP/APA evidence-based 
guidelines for the management of AP (2) as prescribed by the treatment-responsible physician. This includes 
supportive therapy with intravenous fluid therapy (Ringer´s lactate 5-10 ml/kg per hour), enteral feeding 
(elemental or polymeric enteral nutrition formulations via nasojejunal or nasogastric route, alternatively 
parenteral if nasojejunal tube feeding is not tolerated) and analgesics. As the patients will be admitted during 
participation in the study, all concomitant medication and care will be registered in the patient’s medical files 
as with any other patient and subsequently transferred to the CRF. This specifically includes a detailed 
quantification of the need for analgesics (separated into opioids and non-opioids) as this is of great clinical 
significance.  

 
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7.4. Outcomes 
7.4.1. Primary endpoint  
Difference in Pancreatitis activity scoring system (PASS) score between the methylnaltrexone group and the 
placebo group 48 hours after randomization 
7.4.2. Secondary endpoints 
• 
Difference in daily PASS scores between subgroups  
• 
Difference in daily assessments of circulating pro- and anti-inflammatory markers (including CRP, IL-
6, IL-8, IL-18, TNF-α and CD163) as well as intestinal barrier markers between subgroups 
• 
Difference in intestinal permeability between subgroups measured from 48 to 72 hours after 
randomization using the oral polyethylene glycol 400/4000 test  
• 
Difference in intestinal motility assessed by means of gut/colon transit using a CT-based radiopaque 
marker method on day 5 (+/- 1 day) between subgroups 
• 
Difference in pancreatic complications (e.g. edema, fluid collections and necrosis) assessed and 
quantified with contrast-enhanced CT on day 5 (+/- 1 day) after randomization (20)  
• 
Difference between subgroups in the following clinical outcome parameters: pain intensity and gut 
function (assessed by questionnaires), quantification of analgesics (separated into opioids and non-
opioids), need for nutritional support, disease severity, invasive treatments, intensive care and 
hospital stay, as well as mortality during total hospitalization 
• 
Difference in health resource utilization during hospitalization between subgroups 
7.5. Participant timeline  
7.5.1. Study days  
A detailed description of the study procedures is illustrated in Table 1. Patients will be evaluated daily during 
admission by medical personnel and treated in agreement with the IAP/APA evidence-based guidelines for 
the management of AP (2). As part of the study, they will receive daily infusions with methylnaltrexone or 
matching placebo, and have the following examinations performed: i) clinical outcome and patient symptoms 
will be evaluated by means of both well-validated questionnaires and information from the patient’s medical 
records (see section 9.1.2.), ii) the PASS score will be obtained daily and used to document the primary 
endpoint 48 hours after randomization, iii) blood samples (including C-Reactive Protein (CRP), interleukin (IL)-
6, IL-8, IL-18, tumor necrosis factor alpha (TNF-α) and cluster of differentiation 163 (CD163)) will be drawn 

 
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daily with the purpose of evaluating the systemic inflammatory response, and iv) an abdominal contrast-
enhanced CT study will be performed at inclusion and after conclusion of treatment at day 5 (+/- 1 day) to 
document the presence and extent of pancreatic inflammation, fluid collections and necrosis according to 
the definitions given in the revised Atlanta criteria (20). As an integrated part of the CT exam at day 5 (+/- 1 
day) patients will undergo assessment of the colon/gut transit time using radiopaque markers given orally in 
the morning on day 3 up to the planned CT exam. Finally, the intestinal permeability will be evaluated by a 
polyethylene glycol (PEG) 400/4000 test (see section 9.1.5.) 48 hours after randomization. At hospital 
discharge, patients are invited for a follow-up visit on day 14 (+/- 2 days) after randomization where the 
outcomes assessed during hospital admission (blood test and questionnaires including the PASS score) will 
be reassessed. Patients ready for discharge prior to completing five days treatment with methylnaltrexone 
will be handled according to the following:  
• 
< 48 h of treatment: All data collection will be terminated upon discontinuation of the study 
medication and participant is regarded as dropout. 
• 
≥ 48 h of treatment, but discharge before day 5: Participant will be lost to follow-up on the following 
outcomes: daily PASS scores, blood samples, vital signs, quantification of need for analgesics, 
nutritional support, intravenous fluid resuscitation and antibiotics, and data will be analyzed using 
the Last-Observation-Carried-Forward method (see section 9.3.). The participant will be asked to 
complete questionnaires at home and they will be offered a follow-up CT scan in an outpatient 
setting on day 5 (+/− 1 day). Furthermore, they will be invited to participate in the 14-day follow-up 
and readmission rates as well as mortality will be registered retrospectively. 
 
Randomization 
 
Methylnaltrexone or placebo (0.15 mg/kg/day) 
End of study 
Follow-up 
Baseline 
 
24±2 hours 
48±2 hours 
72±2 hours 
96±2 hours 
120±2 hours 
14±2 days 
PASS 
 
PASS 
PASS 
PASS 
PASS 
PASS 
PASS 
Clinical 
outcome 
 
Clinical 
outcome 
Clinical 
outcome 
Clinical 
outcome 
Clinical 
outcome 
Clinical  
outcome 
Clinical  
outcome 
Blood 
samples 
 
Blood 
samples 
Blood 
samples 
Blood 
samples 
Blood 
samples 
Blood  
samples 
Blood  
samples 
 
 
Intestinal 
permeability 
 
 
 
 
 
 
 
 
Intestinal 
transit time 
 
 
 
 

 
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Computed 
tomography 
 
 
 
 
 
Computed 
tomography 
 
 
 
 
 
 
 
Health resource 
utilization 
 
Table 1: Participant timeline. PASS; pancreatitis activity scoring system. 
7.6. Sample size  
We calculated that 41 patients per group will be needed to detect a difference in the PASS score of 25 points 
with a within-group standard deviation of 40 points (22), 80 % power and a 2-sided alfa level of 0.05. Hence, 
the sample size is set at 45 patients per group to allow for possible dropouts.  
7.7. Recruitment 
Patients admitted with AP will be identified and contacted by study personnel upon or during admission. 
Information regarding current and previous medical conditions will be passed on by the treatment-
responsible physician from medical records to study personnel in order to identify eligible patients. This will 
be ensured by study personnel being in daily contact with the staff at the relevant departments at the 
respective inclusion sites with the purpose of monitoring the development of SIRS in patients with AP. This 
will be conducted in accordance to “Sundhedsloven § 46, stk. 1”, under the responsibility of the primary 
investigator at the respective centers. AP is a relatively common disease and thus we expect approximately 
10 patients to be admitted in total every week at our four inclusions sites. We expect at least half of these 
(i.e. 5) to be eligible for participation in the study. 
7.8. Information about the study 
All patients will be informed both oral and written before they decide whether they want to participate in 
the study. Furthermore, they will be informed that they can withdraw from the study at any given time 
without giving a reason. The participants are also allowed to have an assessor with them to the interview. 
Competent delegated personnel (medical doctors affiliated with the study or trained site staff with GCP-
authorization as well as knowledge and experience with the disease involved and conduction of clinical 
randomized placebo-controlled studies) will give the oral information interview according to the Research 
Ethics Committee’s guidelines. The interview will take place in quiet surroundings at one of our respective 
inclusion sites. During the interview, the participant will be informed thoroughly about the purpose of the 
study, the specific procedures the study entails, and potential benefits and risks. Any questions the 
participant have, will also be answered here. 

 
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The written information (“Deltagerinformation”) is given to the participant upon contact. After the interview 
(see section 7.8.), where the participant has received information (oral and written), they are encouraged to 
consider whether they want to participate in the study or not before they sign the informed consent. As these 
patients are admitted with an acute condition the usual requirement of 24 hours for consideration before 
signing the informed consent is not deemed feasible. However, study personnel will ensure that patients will 
have sufficient time to consider participation before signing the informed consent. This includes adequate 
time to discuss with relativities in case the patient wishes to do so. In signing the informed consent, 
participants will be separately asked whether they want to contribute to the establishment of a biobank for 
both blood and urine samples. After the participant has signed the informed consent, they will be randomized 
to either active treatment (methylnaltrexone) or placebo (1:1) and receive an ID-number, which will be 
identical to the randomization-number. For more detailed information about informed consent and 
confidentiality see section 11.4. 
8. Methods: Allocation of interventions  
8.1. Allocation  
Randomization will be conducted by the Hospital Pharmacy at Herlev Hospital in blocks of random size(block-
randomization), using approved statistical software e.g. from the website www.randomization.com. A 
specific randomization will be assigned by the Hospital Pharmacy to the individual patient once study 
personnel have completed inclusion. This randomization number will be returned to study personnel, which 
alongside with participants will be blinded to the allocation. None of the collected data are expected to 
unblind the randomization. Methylnaltrexone and matching placebo will be ordered at and delivered by The 
Hospital Pharmacy to the respective investigational sites. All medication will be labeled with the 
randomization number corresponding the allocation as well as the information that it is intended for use in 
a clinical trial only. All sites will have trained personnel to carry out a documented acceptance testing to 
ensure the right delivery and to keep a strict study medication account.   
8.2. Blinding  
The study is double-blinded, and the blinding will be conducted by the Hospital Pharmacy at Herlev Hospital. 
This way of blinding will ensure that personnel involved in the project and participants included in the study 
are prevented from knowing information that might lead to bias of the results. All study medication will be 
labelled indicating “study medication”, “id”, “initials”, “period”, “daily dosing paradigm” and “contact 
information”. Labelling will be performed by the Hospital Pharmacy at Herlev Hospital, according to Annex 

 
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13 of the Good Manufacturing Practice guidelines of the European Commission, ICH, GCP guidelines, and 
local law. 
In case of an medical emergency (e.g. SUSAR, see section 10.2.3.) that necessitates knowledge of the 
treatment randomization, the individual treatment assignment for each subject will be available at each 
study center in sealed envelopes (provided by The Hospital Pharmacy) stored in a secure area accessible to 
study personnel allowed by the investigator to open the code for a single subject. The other study centers 
can always get in contact with the primary study center by a provided phone number in case of a situation 
where unblinding is necessary. This procedure allows unblinding of individual subjects, without revealing 
codes of the entire study. Thus, the study personnel will be able to determine which treatment a particular 
subject was given by opening the sealed envelope with the corresponding randomization number. The 
investigator must state the reason why the code was broken on the envelope, date and sign it.  
A subject that discontinues will be asked about the reason(s) for discontinuation and the presence of any 
adverse events but are not obliged to provide this information.  If needed, they will be seen and assessed by 
a medical doctor affiliated with the study. Dropouts will be replaced by new subjects and a mirror 
randomization will be performed i.e. they are part of the same randomization, but with a new number (e.g. 
101 replaces 1 etc.). 
Patients with AP will be admitted while participating in the study and hence have the study medication 
(Relistor® or matching placebo) administered to them by medical professionals. The medication and 
placebo will be delivered to the medical staff from the Hospital Pharmacy at Herlev Hospital in the form of 
fluid for infusion with similar appearance, so that the medical staff treating the patient will remain blinded.  
 
9. Methods: Data collection, management, and analysis 
9.1. Data collection methods 
9.1.1. Pancreatitis Activity Scoring System  
PASS is a validated assessment tool for AP based on five clinical parameters, which are weighed according to 
figure 2 (23). It quantitatively evaluates the course of AP and has proven useful for monitoring disease 
severity as well as predicting clinical outcome in patients admitted with AP (22). Organ failure (i.e. renal, 
respiratory and cardiovascular) will be assessed according to the Modified Marshall scoring system as defined 
in the Revised Atlanta criteria (20). Thus, organ failure of the cardiovascular and renal system, is assessed by 

 
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means of systolic blood pressure and serum creatinine respectively. The ratio between 
partial pressure of oxygen in arterial blood (PaO2) and the fraction of inspired oxygen (FiO2) is used to assess 
the respiratory system. Not all participants included into this study are expected to have PaO2 values 
available. Thus, we will use the ratio between peripheral capillary oxygen saturation (SpO2) and FiO2 instead, 
as previous studies have shown that these two ratios correlate well (24,25).  
 
 
Figure 2: Pancreatitis Activity Scoring System (PASS) 
9.1.2. Clinical outcome and health resource utilization  
Clinical outcomes and health resource utilization are documented using preformed questionnaires and by 
means of the medical records. Thus, participants will be asked to fill out three questionnaires daily: i) The 
modified Brief Pain Inventory short form, ii) Bristol Stool Form Scale and iii) Gastrointestinal Symptom Rating 
Scale (GSRS). For a detailed description of these, see below. From the patients’ medical records, the following 
will be registered: i) presence of local and systemic complications as well as organ failure (transient or 
persistent), used to classify the severity of AP according to the revised Atlanta criteria (20), ii) need for 
intensive care unit admission, iii) need for analgesics, iv) nutritional support, v) invasive treatment, vi) 
duration of hospitalization, and vii) mortality. Total duration of hospitalization, readmission rates and 
mortality will be determined retrospectively 30 and 90 days after admission using the patients’ medical 
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9.1.3. Questionnaires 
9.1.3.1. The modified Brief Pain Inventory short form 
The modified Brief Pain Inventory short form is used to subjectively document patients’ pain intensity at a 
visual analogue scale from 0-10  as well as relief from medication and impact on daily functions (interference 
score) (26).  
9.1.3.2. Bristol Stool Form Scale 
The Bristol Stool Form Scale is an objective assessment of parameters such as stool frequency as well as stool 
consistency and is used to assess intestinal function (27). 
9.1.3.3. Gastrointestinal Symptom Rating Scale   
The Gastrointestinal Symptom Rating Scale (GSRS) is a disease-specific instrument of 15 items combined into 
five symptom clusters depicting reflux, abdominal pain, indigestion, diarrhea and constipation. The GSRS has 
a seven-point graded Likert-type scale, where 1 represents absence of troublesome symptoms and 7 
represents very troublesome symptoms. The reliability and validity of the GSRS are well-documented, and 
normal values for a general population are available (28). 
9.1.4. Biochemistry  
Patients with AP will have daily blood samples drawn with the purpose of measuring the systemic 
inflammatory response (including CRP, IL-6, IL-8, IL-18, TNF-α and CD163). Blood samples (31 ml blood per 
timepoint) will be drawn at baseline and daily at fixed time points for five consecutive days and two weeks 
after study termination. Blood samples will be separated by centrifugation and processed as plasma, serum, 
buffy coat and full blood and subsequently transferred in aliquots to vials labeled with the protocol number 
(PAMORA_2020), subject number, and date of sample collection. Samples will be frozen and stored at 
approximately -80°C or cooler in a freezer at the respective inclusion sites until analysis. The samples will be 
batch analyzed at a central laboratory to measure the analytes of interest. During the entire study period, a 
total of 186 ml of blood will be drawn from each AP participant. 
After the analyses, all blood samples from both groups of patients will be kept in a biobank for future research 
purposes and destroyed at the latest 15 years after termination of the study. Ethics according to 
“databeskyttelsesforordningen” and ”databeskyttelsesloven” will be ensured in this regard. 
9.1.5. Imaging 
Patients with AP will have an abdominal contrast enhanced CT scan performed at baseline and after 5 days 
(+/- 1 day) of treatment. Morphological changes related to AP will be evaluated and described according to 
the terminology and definitions of the revised Atlanta criteria and the modified CT severity index (20,29). 

 
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Furthermore, as an integrated part of the CT exam at day 5 (+/- 1 day) patients will undergo assessment of 
the intestinal transit time using radiopaque markers given orally on day 3 prior to the CT exam. 
9.1.6. PEG 400/4000 test  
Measurement of intestinal permeability and mucosal integrity in patients with AP, will be performed using   
the oral PEG 400/4000 test (30). In case of intestinal barrier function loss (a leaky gut), the large size 
molecules (PEG 4000) cross the intestinal barrier, appear into the circulation and becomes detectable in urine 
after renal excretion. The small size molecules (PEG 400) traverse the intestinal barrier freely, independent 
of barrier function loss, but is affected in the same way as the large molecules by the pre- and post-mucosal 
processes including gastric dilution, gastrointestinal motility, bacterial degradation, and renal function. 
Therefore, the ratio of the urinary concentration of both molecules (PEG 400/4000) more accurately reflect 
the intestinal permeability and integrity than isolated measurement of a single molecule (31). A PEG solution 
containing 5 g PEG 400 and 5 g PEG 4000 dissolved in 100 mL water, will be prepared. 48 hours after 
randomization, the PEG solution is enterally administered via oral intake or a feeding tube and followed by 
24-hour urine output collection. Upon collection urine will be homogenized and centrifuged. The supernatant 
will be desalted by ion-exchange and transferred in aliquots to vials labeled with the protocol number 
(PAMORA_2020), subject number, and date of sample collection, which will subsequently be frozen and 
stored at approximately -80°C or cooler at the respective inclusion sites. Urine samples will be analyzed at a 
central laboratory to measure the analytes of interest. Excess urine samples will be kept frozen for future 
research purposes, thereby establishing a biobank. All samples will be destroyed at the latest 15 years after 
termination of the study. Ethics according to “databeskyttelsesforordningen” and  ”databeskyttelsesloven” 
will be ensured in this regard.  
9.2. Data management  
The study will be submitted to the Northern Region of Denmark (“Forskningsanmeldelse Region Nordjylland 
– Registrering af forskningsprojekter”). Standard operating procedures (SOPs) for data handling and record 
keeping exists within the research center and these will be followed. 
The principal investigator must maintain complete and accurate records to ensure that the execution of the 
study is fully documented, and the study data can be subsequently verified. These documents should be 
classified in 2 separate categories: i) researcher Trial Master File and ii) study/participant's clinical source 
documents (case report form). 
Redcap, a secure browser-based software, will be used for filling in the eCRF form for each participant. 
RedCap meets all regulatory safety requirements and is approved for data collection by the North Danish 

 
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Region. Data recording will begin when a participant is included and will occur gradually to the end of the 
study trial. Any corrections will be made in such a way that information from the original version is still 
available. The changes endorsed by initials and date. All forms are filled out during (or immediately after) the 
assessment of a participant and must be legible.  
Data will be stored at Aalborg University Hospital, Department of Medical Gastroenterology, for a minimum 
of 5 years after the study has ended. Relevant information from the participants’ medical records will be 
given to the investigator if needed to assess the in- and exclusion criteria. After five years all data will be 
anonymized. 
The trial master file must contain the protocol/amendments, correspondence with the Danish Health and 
Medicines Authority, The North Denmark Region Committee on Health Research Ethics and Danish Data 
Protection Agency, informed consent, staff curriculum vitae, forms, delegation-log, and other appropriate 
documents/correspondence etc.  
The principal investigator at each study site, allows direct access to all source data and documents at 
monitoring, auditing, and inspection from the Danish Health and Medicines Authority or The Danish Data 
Protection Agency as well as the GCP-unit at Aalborg and Aarhus University Hospital. 
A participant identification list is created for all persons included in the study. This list contains patient 
number, full name and civil registration number. The list is populated and updated by a study nurse or other 
competent person and is stored at Department of Gastroenterology, Aalborg University Hospital. 
9.2.1. Case report forms  
Data related to the primary outcomes (PASS score), clinical outcome and health resource utilization will be 
entered directly into electronic CRFs using REDCap, licensed by Aalborg University Hospital, and saved 
electronically. All forms are filled out during (or immediately after) the assessment of a subject and must be 
legible. Errors and corrections are logged as provided by the REDCap interface. It is possible to export 
validated data from REDCap to e.g. a statistical program (e.g. STATA) for further statistical analysis. When 
data have been entered, reviewed, and verified the data will be frozen to prevent editing. Digitalized data 
are backed up and stored on specific drives at each site under the responsibility of the principal investigators 
for a minimum of 5 years after the study has ended.  
9.2.2. Source data identification and protection 
A Patient Identification List containing patient number, full name, civil registration number for all participants 
included in the study is created, and ethics according to “databeskyttelsesforordningen” and 
”databeskyttelsesloven” is ensured. The list is populated and updated by a project nurse or other competent 

 
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person. A list of all source documents will be devised at the initiation of the study. All source documentation 
will be stored on a secure drive under the responsibility of the principal investigator. 
9.3. Statistical methods  
A repeated measures linear mixed effects model will be used for the primary analysis and will include terms 
for treatment group, assessment time point (day after randomization), and the interaction of treatment with 
assessment time point. Summary statistics and trend curves of PASS scores will be provided for the individual 
time points, and the difference in PASS scores between groups 48 hours after randomization is considered 
the primary efficacy parameter. Subgroup and covariate analyses will be performed if applicable and in case 
differences in patient subgroups deemed clinically relevant are evident. The primary analysis will be by 
intention to treat and in case of early hospital discharge or other reasons for missing values, the Last-
Observation-Carried-Forward method will be employed. Trends in PASS and other secondary endpoints 
assessed consequently during the treatment period (biochemical tests and clinical outcome parameters) are 
analyzed using linear random-effects models and results presented as fitted trend curves. Outcomes assessed 
at single time points (baseline characteristics, CT features and gut permeability) are compared using 
Student´s t-test or non-parametric analysis for continues data as appropriate. Binary outcomes will be 
analyzed using Fisher’s exact test. All secondary endpoints will be analyzed by per-protocol.  
9.3.1. Criteria for the termination of the trial 
The trial is terminated when full datasets for 90 patients with AP has been collected.  
9.3.2. Missing data 
Handling of missing data will be defined in the final statistical analysis plan and finalized before unblinding of 
data.  
9.3.3. Deviations from the original statistical plan 
It will be reported if any deviations from the original statistical plan occur. 
10. Methods: monitoring  
10.1. GCP monitor  
A monitor will be allocated from the good clinical practice (GCP) unit at Aarhus and Aalborg University 
Hospitals, and an agreement between Aalborg University Hospital and the GCP unit will be signed. The 
responsible monitor will contact and visit the principal investigator on a regular basis. The monitor will be 
authorized to inspect the different study records (CRFs, source data/documents and other relevant data), 
provided that the subjects' information is kept confidential in accordance with the data protection agency 

 
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conditions. It will be the responsibility of the monitor to inspect CRFs regularly throughout the study to 
ensure compliance and completion of the protocol and that consistent and accurate data is entered in these. 
Monitor will check and verify that each subject has given written informed consent for direct access to study 
records as well as study procedures. Principal investigator (or his/her representative) agrees to cooperate 
with the monitor to ensure that all potential problems, discovered during the monitor’s visit, will be solved. 
Investigator provides direct access to source data/documents (including medical records) during monitoring, 
auditing and/or inspection by the Danish Medicines Agency or The Danish Data Protection Agency.  
10.2. Assessment of safety and harms 
10.2.1. Adverse event and adverse reaction 
An adverse event (AE) is according to the ICH-guideline defined as “any untoward medical occurrence in a 
patient administered a medicinal product and which does not necessarily have to have a causal relationship 
with this treatment” and can be expected as well as unexpected. An adverse reaction (AR) concerns noxious 
and unintended responses to a medical product, meaning that a causal relationship between a medical 
product and an AE is at least a reasonable possibility. As these patients are acutely ill and admitted to hospital 
during participation in the study, they are expected to have certain symptoms and laboratory result 
deviations frequently associated with the disease. These are listed below:  
Symptoms  
Laboratory result deviations  
 
abdominal pain  
elevated plasma amylase or lipase 
nausea 
elevated plasma CRP  
vomiting 
elevated serum creatinine 
 
elevated serum liver enzymes and/or bile acids  
 
elevated blood sugar levels  
 
elevated white blood cell count  
 
These will not be reported as AE's as well as AE’s assessed clinically insignificant will not be reported. The 
evaluation hereof will fall upon study-affiliated doctors assessing the individual patient under the 
responsibility of the primary investigator. AE’s and AR’s will be registered for 45 hours after the study 
medication is discontinued. This corresponds five times the half-life of Methylnaltrexone (Relistor ®) which 
is 8-9 hours (32). Any AE or AR fulfilling the criteria for serious (SAE/SAR) will be reported according to the 
descriptions below. All expected and un-expected AEs and ARs to be reported, will be registered in the CRF 
and included in a final report which will be registered into EudraCT along with the results at the trial’s 
termination. Information about AEs will be collected from the first administration of any investigational 
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10.2.2. Serious adverse event or serious adverse reaction 
A serious adverse event (SAE) or a serious adverse reaction (SAR) is an AE or AR occurring during the study 
phase that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (NOTE: the term “life threatening” in the definition of serious refers to an 
event/reaction in which the subject is at risk of death at the time of the event/reaction; it does not 
refer to an event/reaction which hypothetically might have caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization (planned hospitalization 
is not to be reported as SAE or SAR) 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect despite birth control during the study 
All SAEs and SARs will be registered and reported to the sponsor by primary investigator as described below. 
A SAR is unexpected (i.e. suspected unexpected serious adverse reaction, SUSAR) if it is not consistent with 
the description in the medicinal product source document. The Research Ethics Committee and Danish 
Medicines Agency will annually be presented with a list of all SAR and SUSAR that have occurred during the 
trial as well as an evaluation of patient safety until the trial has concluded. All fatal or life threatening SUSARs 
are reported to the Danish Health and Medicines Authority and The Research Ethics Committee as soon as 
possible and no later than 7 days after the sponsor has been notified of SUSAR.  
Investigator must report any SAE, SAR, or SUSAR to the sponsor immediately (within 24 hours) in order for 
sponsor to report to the Danish Healthy and Medicines Authority in time. As patients with AP often 
experience serious complications during admission as part of the disease, the list below entails SAEs that will 
not be reported to sponsor immediately (non-immediate reporting). These will instead be reported to 
sponsor within no more than 7 days:  
• 
Sepsis or septic shock  
• 
Kidney failure  
• 
ARDS (acute respiratory distress syndrome) 
Within 7 days after reporting of SUSAR, the sponsor must notify the Danish Health and Medicines Authority 
about all relevant information of the sponsor and investigator’s follow-up on the SUSAR. All other SUSARs 

 
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should be reported to the Danish Health and Medicines Authority within 15 days after the sponsor has been 
notified of the SUSAR. SUSAR’s will be unblinded prior to any report to authorities. 
All SUSARs will be reported electronic to the Danish Health and Medicines Authority using the following e-
form on their home page: “Reporting of suspected unexpected serious adverse reactions (SUSARs) seen in 
clinical trials”. Additionally, all SUSARs must immediately be notified to The Research Ethics Committee. Any 
report must be accompanied with comments regarding possible consequences for the trial. The assessment 
of SUSAR will be made before unblinding.  
10.2.3. Safety follow-up procedure 
All SAE´s and related AE´s must be followed-up until the event has resolved or stabilized, or the relationship 
to study medication is clarified. All participants with unresolved events at the end of the study, except those 
who dropped out before randomization or starting active treatment, must be included in a safety follow-up 
visit in order to check response of events to de-challenge. The safety follow-up visit should take place one to 
two weeks after the Final Examination / Premature Termination. Events, which are not complete in this way 
by the end of the period of observation, must be followed-up on until this status has been achieved. Follow-
up can be wavered in specific cases after consultation with sponsor. This permission must be documented 
per case and retained in the investigator site file and trial master file. 
10.3. Quality control and quality assurance 
Quality Control is defined as the operational techniques and activities undertaken within the quality 
assurance system to verify that the requirements for quality of the study related activities have been fulfilled. 
Quality Control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly, according to standard CGP-guidelines.  
Quality Assurance is defined as the planned and systematic actions that are established to ensure that the 
study is performed, and the data are generated, documented (recorded), and reported in compliance with 
GCP and the applicable regulatory requirements. An independent audit at the study site may take place at 
any time during or after the study. The study will be monitored by an independent company/person not 
otherwise involved in the project. Furthermore, monitoring visits to the trial site will be made periodically 
during the trial to ensure that all aspects of the protocol are followed. Source documents will be reviewed 
for verification of agreement with data on CRFs. The Investigator/institution guarantees direct access to 
source documents to appropriate regulatory agencies. The trial site may also be audited (quality assurance) 
or inspected by appropriate regulatory agencies. It is important that the investigator and their relevant 

 
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personnel are available during the monitoring visits and possible audits and that enough time is devoted to 
the process. 

 
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11. Ethics and dissemination  
This clinical study will be conducted in compliance with Good Clinical Practice (CPMP/ICH/135/95), 
designated Standard Operating Procedures, the Danish Medicines Agency, the North Denmark Region 
Committee on Health Research Ethics, and within the principles of the Declaration of Helsinki (amended by 
the 64th WMA General Assembly, Fortaleza, Brazil, October 2013). Additionally, this study will be undertaken 
in accordance with the Protocol and Good Clinical Practice on the conducting and monitoring of clinical 
studies. The trial will only be initiated once the approvals from the North Denmark Region Committee on 
Health Research Ethics and the Danish Medicines Agency are given. Any significant modifications to the 
protocol, will be submitted as protocol amendments and subsequently approved by the North Denmark 
Region Committee on Health Research Ethics and the Danish Medicines Agency before implementation.  
11.1. Risks related to the experimental procedures 
Biochemical tests including blood samples, PEG 400/4000 test, bear little risk for the patients and 
furthermore are all part of the standard evaluation of these diseases.  
CT-scans involve radiation and careful consideration should always be applied when using this modality in 
clinical research. Patients admitted with AP will have CT-scans performed upon admission and at 5 day follow 
up (+/- 1 day). In Denmark, the estimated average radiation dose from one CT-scan of the abdomen is 11,9 
millisievert (mSV) (33). Thus, the modality bears significant risk for individuals participating in the study. It is 
part of the standard diagnosis strategy to perform a CT-scan on patients admitted with symptoms of AP and 
many patients will have a follow up CT-scan prior to discharge to evaluate the presence of complications 
including pancreatic necrosis and fluid collections. The CT-scans will also be available for the attending 
physicians. Furthermore, we expect the utility of the data collected to potentially promote prevention and 
better treatment of AP, which is a severe medical condition. Hence, we find it ethically sound to perform the 
study as described.  
11.2. Risks related to study medication 
Treatment with PAMORA may be uncomfortable for patients as they may experience side effects like 
diarrhea or nausea. PAMORAs, especially methylnaltrexone, can worsen the clinical course of intestinal 
stenosis, because they increase motility and secretion in the intestine. At worst, this can cause perforation 
of the intestines which can be fatal. This has been accounted for in the exclusion criteria (see section 7.2.2.). 
Participation in the study will be potentially beneficial for patients with AP receiving active medication and it 
is expected that this study will produce important knowledge on the treatment of AP for future patients. In 

 
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this regard, the use of placebo is crucial for evaluating the true effect of PAMORAs on the course of disease. 
Furthermore, all patients, regardless of whether they receive active treatment or placebo, may gain new 
insights and understanding into the pathophysiology of their disease and possible beneficial future 
treatment. The treatment of patients receiving placebo will not be affected by participation in the study as 
they still receive standard treatment.  
In conclusion, the risk the participants are exposed to in this study is minimal compared to the beneficial 
information that will be gained from the study – both for the individual patient, but also for future treatment 
of patients with AP. 
11.3. Patient insurance  
Clinical responsibility befalls the University Hospitals involved in the study. All participants will be covered by 
the patient insurance of the respective site of trial conduction. Participation in a trial involving medical 
treatment may alter private insurance status, should the participant wish to travel during or right after study 
participation. Participants are advised to seek consultancy from their insurance agency if they plan to travel 
during or right after participation in the study. 
11.4. Consent and confidentiality     
The informed consent will be obtained following oral and written information has been given by competent 
delegated study personnel as previously described in section 7.8. Once informed consent is signed, this allows 
investigators; monitors from The Good Clinical Practice Unit at Aalborg and Aarhus University Hospitals; GCP 
inspection; and Danish Health as well as Medical Authority to assess patients’ medical records with the 
purpose of retrieving information necessary for study conduction, monitoring and inspection. Detailed 
clinical characterization of the patient, complementary information in relation to the study will be made 
available from medical records so that sponsor and monitor can control the quality of the study regarding 
“informationsbekendtgørelsen”. 
Information 
about 
participants 
is 
protected 
by 
”databeskyttelsesforordningen”, ”databeskyttelsesloven”, and ”sundhedsloven”. 
11.5. Declaration of interests  
None.  
11.6. Access to data  
The trial will be registered at clinicaltrialregister.eu and EudraCT, and at the end of the study, the results will 
also be published at these websites. All results will be published as open access whenever possible using both 

 
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scientific and public media. When the clinical trial ends, the anonymized data will be made available to other 
researchers through relevant and actual public databases such as Zenodo. 
11.7. Dissemination policy 
Results, positive as well as negative and inconclusive, will be released to the public, and may be published in 
peer-reviewed scientific journals. Results may also be used in submission to regulatory authorities. The first 
author will be appointed according to the Vancouver system. The investigator will inform the Danish 
Medicines Agency and the Research Ethics Committee after the termination of the trial. No later than 90 days 
after trial termination, the “Declaration of the end of trial form” must be submitted to The Danish Medicines 
Agency, and as soon as possible or within 1 year the results will be registered with EudraCT. The Research 
Ethics Committee will be notified of results from this study. Published articles are sent to The Danish 
Medicines Agency and the Research Ethics Committee. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

 
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