Neurotoxic Adverse Effects of Morphine and Oxycodone in Continuous Subcutaneous Infusion for Treatment of Pain in Terminal Patients With Diminished Renal Function: a Randomized Controlled Trial
Phase: PHASE4
Conditions: Pain, Terminal Illness, Renal Impairment
Sponsor: Maastricht University Medical Center

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RESEARCH PROTOCOL 
 
 
 
MOSART-study 
 
 
Neurotoxic adverse effects of morphine and oxycodone 
in continuous subcutaneous infusion for treatment of 
pain in terminal patients with diminished renal function:  
a Randomized Controlled Trial. 
 
 
 
 
 
MJM Martens1,2, MHJ van den Beuken-van Everdingen1,3, DJA Janssen1,4, SMJ van Kuijk5, 
JMGA Schols2,6. 
 
 
1 Centre of Expertise in Palliative Care MUMC+ (EPZM), Maastricht University Medical Centre (MUMC+), Maastricht, The 
Netherlands 
2 Envida, Maastricht, The Netherlands 
3 University Pain Centre Maastricht (UPCM), Department of Anesthesiology and Pain Management, Maastricht University 
Medical Centre (MUMC+), Maastricht, The Netherlands 
4 CIRO+, Centre of Expertise in Chronic Organ Failure, Horn, The Netherlands 
5 Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Centre 
(MUMC+), Maastricht, The Netherlands 
6 Department of Health Services and Ageing, Care and Public Health Research Institute (CAPHRI), Maastricht University 
Medical Centre (MUMC+), Maastricht, The Netherlands 
7 Department of Family Medicine, Care and Public Health Research Instituate (CAPHRI), Maastricht University Medical Centre 
(MUMC+), Maastricht, The Netherlands 
 
 

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Neurotoxic adverse effects of morphine and oxycodone in continuous subcutaneous  
infusion for treatment of pain in terminal patients with diminished renal function: a 
Randomized Controlled Trial.  
 
Protocol ID 
METC172020 
Short title 
MOSART-study 
(Morphine vs. Oxycodone for Subcutaneous infusion: 
Adverse effects in Renally impaired Terminal patients) 
EudraCT number  
2017-002192-25 
Version 
3 
Date 
2017.10.18 
Coordinating investigator/project 
leader 
 
Drs. M.J.M. Martens 
Elderly care phycisian/consultant palliative care 
MUMC+ 
PO Box 5800 
6202 AZ Maastricht 
The Netherlands 
0031(0)630605958 
mark.martens@mumc.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Prof. dr. M.H.J. van den Beuken-van Everdingen 
Internist/consultant palliative care 
MUMC+ 
PO Box 5800 
6202 AZ Maastricht 
The Netherlands 
0031(0)43 3877392 / 0031(0)651363776 
m.vanden.beuken@mumc.nl 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Academic Hospital Maastricht (in Dutch: ‘Academisch 
Ziekenhuis Maastricht’) 
Profit centre ‘Patient and Care’ (in Dutch: RVE 
‘Patiënt en Zorg’) 
Centre of Expertise in Palliative Care 

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Subsidising party 
ZonMw 
Independent expert(s) 
Dr. med. M.N. Janssen, FIPP 
anesthesiologist/pain expert 
MUMC+ 
P. Debyelaan 25 
6229 HX Maastricht 
0031(0)43 3875606 
Laboratory sites 
Centraal Diagnostisch Laboratorium MUMC+ 
0031(0)43 3876703 
onderzoeksprojecten.cdl@mumc.nl 
Pharmacy 
Not applicable 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
 
Dr. J.F.B. Fiolet 
Director profit centre ‘Patient 
and Care’ (in Dutch: RVE 
‘Patiënt en Zorg’) MUMC+ 
 
 
 
 
Principal Investigator: 
Prof dr. M.H.J. van den 
Beuken-van Everdingen 
Internist/consultant palliative 
care MUMC+ 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................14 
3. 
STUDY DESIGN ...........................................................................................................15 
4. 
STUDY POPULATION ..................................................................................................17 
4.1 
Population (base) ...................................................................................................17 
4.2 
Inclusion criteria .....................................................................................................17 
4.3 
Exclusion criteria ....................................................................................................18 
4.4 
Sample size calculation ..........................................................................................18 
5. 
TREATMENT OF SUBJECTS .......................................................................................20 
5.1 
Investigational product/treatment ............................................................................20 
5.2 
Use of co-intervention ............................................................................................20 
5.3 
Escape medication .................................................................................................20 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................21 
6.1 
Name and description of investigational product(s) ................................................21 
6.2 
Summary of findings from non-clinical studies ........................................................21 
6.3 
Summary of findings from clinical studies ...............................................................21 
6.4 
Summary of known and potential risks and benefits ...............................................22 
6.5 
Description and justification of route of administration and dosage .........................22 
6.6 
Dosages, dosage modifications and method of administration ...............................22 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................22 
6.8 
Drug accountability .................................................................................................22 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................23 
8. 
METHODS ....................................................................................................................24 
8.1 
Study parameters/endpoints ...................................................................................24 
8.1.1 
Main study parameter/endpoint .......................................................................24 
8.1.2 
Secondary study parameters/endpoints ..........................................................24 
8.1.3 
Other study parameters ...................................................................................25 
8.2 
Randomisation, blinding and treatment allocation ..................................................25 
8.3 
Study procedures ...................................................................................................26 
8.4 
Withdrawal of individual subjects ............................................................................29 
8.4.1 
Specific criteria for withdrawal .........................................................................29 
8.5 
Replacement of individual subjects after withdrawal ...............................................30 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................30 
8.7 
Premature termination of the study .........................................................................30 
9. 
SAFETY REPORTING ..................................................................................................31 
9.1 
Temporary halt for reasons of subject safety ..........................................................31 
9.2 
AEs, SAEs and SUSARs ........................................................................................31 
9.2.1 
Adverse events (AEs) ......................................................................................31 
9.2.2 
Serious adverse events (SAEs) .......................................................................31 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................33 
9.3 
Annual safety report ...............................................................................................35 

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9.4 
Follow-up of adverse events ...................................................................................35 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..................................35 
10. 
STATISTICAL ANALYSIS ..........................................................................................36 
10.1 
Primary study parameter(s) ....................................................................................37 
10.2 
Secondary study parameter(s) ...............................................................................37 
10.3 
Interim analysis ......................................................................................................37 
11. 
ETHICAL CONSIDERATIONS ...................................................................................38 
11.1 
Regulation statement .............................................................................................38 
11.2 
Recruitment and consent........................................................................................38 
11.3 
Objection by incapacitated subjects .......................................................................39 
11.4 
Benefits and risks assessment, group relatedness .................................................39 
11.5 
Compensation for injury .........................................................................................40 
11.6 
Incentives ...............................................................................................................40 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................41 
12.1 
Handling and storage of data and documents ........................................................41 
12.2 
Monitoring and Quality Assurance ..........................................................................41 
12.3 
Amendments ..........................................................................................................42 
12.4 
Annual progress report ...........................................................................................42 
12.5 
Temporary halt and (prematurely) end of study report ............................................42 
12.6 
Public disclosure and publication policy ..................................................................43 
13. 
STRUCTURED RISK ANALYSIS...............................................................................44 
13.1 
Potential issues of concern .....................................................................................44 
13.2 
Synthesis ...............................................................................................................44 
14. 
REFERENCES ..........................................................................................................45 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application form 
that is required for submission to the accredited Ethics Committee (In Dutch, 
ABR = Algemene Beoordeling en Registratie) 
ADR 
European Agreement concerning the International Carriage of Dangerous 
Goods by Road; in French: Accord européen relatif au transport international 
des marchandises Dangereuses par Route 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease EPIdemiology collaboration 
COV 
Close-Out Visit 
CRF 
Case Report Form 
CSCI 
Continuous Subcutaneous Infusion 
CTCM 
Clinical Trial Center Maastricht 
CV 
Curriculum Vitae 
DOS 
Delirium Observation Screening 
DSM-IV-
TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision 
DSMB 
Data Safety Monitoring Board 
eGFR 
Estimated Glomerular Filtration Rate 
EORTC 
QLQ-C30 
European Organization for Research and Treatment of Cancer-Quality of Life 
Questionnaire-Core 36 
EudraCT 
European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICH-GCP 
ICH Good Clinical Practice 
IKNL 
Netherlands Comprehensive Cancer Organisation; in Dutch: Integraal 
Kankercentrum Nederland 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  

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IMV 
Interim Monitoring Visit 
KNMG 
Royal Dutch Medical Association; in Dutch: Koninklijke Nederlandsche 
Maatschappij tot bevordering der Geneeskunst 
KNMP 
Royal Dutch Pharmacists Association; in Dutch: Koninklijke Nederlandse 
Maatschappij ter bevordering der Pharmacie 
M3G/M6G 
Morphine-3-Glucuronide / Morphine-6-Glucuronide 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
MUMC 
Maastricht University Medical Centre; in Dutch: Maastricht Universitair Medisch 
Centrum 
NMDA 
N-methyl-D-aspartate 
NRS 
(0-10 Verbal) Numeric Rating Scale 
NTAE 
Neurotoxic Adverse Effects 
OIH 
Opioid Induced Hyperalgesia 
OR 
Odds Ratio 
PG 
PsychoGeriatric 
QoDD 
Quallity of Dying and Death 
REPOS 
Rotterdam Elderly Pain Observation Scale 
RCT 
Randomized Controlled Trial 
ROO 
Rapid-Onset Opioid 
(S)AE 
(Serious) Adverse Event  
SIV 
Site Initiation Visit 
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-
tekst) 
Sponsor 
The sponsor is the party that commissions the organisation or performance of 
the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
WBP 
Personal Data Protection Act; in Dutch: Wet Bescherming Persoonsgevens 
WGBO 
Dutch Medical Treatment Act; in Dutch: Wet op de Geneeskundige Behandel 
Overeenkomst 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 

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SUMMARY 
 
Rationale: The prevalence of significant pain at the end of life is high. Continuous 
subcutaneous infusion (CSCI) of opioids is the cornerstone in treatment of pain in this last 
phase of life. Although morphine is the most frequent used opioid in this respect, its main 
metabolites – morphine-3-glucuronide (M3G) and morphine-6-glucuranide (M6G) – start to 
accumulate when renal function decreases. The accumulation of M3G is associated with 
neurotoxic adverse effects like delirium, allodynia and hyperalgesia. The central effects of 
circulating metabolites of oxycodone, on the other hand, are negligible. On theoretical 
considerations CSCI of oxycodone for the treatment of pain in dying patients with a 
diminished renal function should therefore result in a reduced occurrence of the neurotoxic 
adverse effects delirium and allodynia/hyperalgesia in comparison to morphine. However, 
studies of sufficient quality investigating the clinical effect of this hypothesis are lacking at the 
moment. 
Objective: The primary objective of this study is to compare the prevalence of delirium 
between oxycodone and morphine, administered by CSCI, for the treatment of pain in dying 
patients with a diminished renal function. The secondary objective is to compare the 
prevalence of allodynia/hyperalgesia between these two opioids. 
Study design: A randomized, controlled, observer blinded, multicentre, superiority trial with 
to parallel groups with an 1:1-allocation-ratio. 
Study population: Residents of hospices and somatic or psychogeriatric (PG) wards of 
nursing homes, 18 years or older, who are eligible for start of CSCI of an opioid for the  
treatment of pain in the terminal phase of life. 117 patients per group are needed. 
Intervention: One group receives CSCI of oxycodone and the other group CSCI of 
morphine. 
Main study parameters/endpoints: The main study parameter is the difference in 
occurrence of delirium at any time between start of CSCI of morphine or oxycodone and 
death. The secondary parameter is the difference in occurrence of allodynia/hyperalgesia. 
The Delirium Observation Screening (DOS)-scale is used for screening for presence for 
delirium. The clinical diagnosis of delirium is confirmed or rejected in accordance with the 
DSM-IV-TR criteria. Brushing with a piece of cotton wool on the skin and pin-prick testing is 
performed to assess for presence of allodynia/hyperalgesia. Items of the Rotterdam Elderly 
Pain Observation Scale (REPOS) are used to determine presence of pain in subjects who 
are verbally inadequate responsive. All parameters are assessed three times a week until 
death of the participant. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Since the investigated products are registered products to be used in 

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regular care for the registered indication and route of administration, and not in combination 
with other products, participants are not exposed to any additional medication-related risks. A 
one-time blood collection by venipuncture at the first visit is performed to assess renal 
function. The risk of venepuncture-related complications is considered low. The burden 
associated with assessment for delirium and allodynia/hyperalgesia three times a week is 
considered low. It is essential to not exclude an incapacitated (psychogeriatric) population in 
this study to best represent usual care, since the major part of dying patients experiences a 
decline in cognitive functions and are not able to respond adequately anymore. Special 
attention will be paid to signs of objection or resistance to any of the study procedures by 
incapacitated subjects. 
 

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1. INTRODUCTION AND RATIONALE 
The prevalence of significant pain at the end of life has been estimated to be around 50% in 
the last 1-2 months prior to death and 30-75% in the last days of life (1-4). Continuous 
subcutaneous infusion (CSCI) of opioids has become the cornerstone in treatment of pain in 
dying patients (5, 6). Both continuous subcutaneous administration by a syringe driver and 
scheduled intermittent subcutaneous injections are equal in analgesic effectiveness and side 
effects (7).  Morphine is the most frequent used opioid in this respect (8, 9). 
 
Morphine, metabolites and renal impairment 
The two major metabolites of morphine are morphine-3-glucuronide (M3G) and morphine-6-
glucuronide (M6G). These two metabolites are excreted renally (10). Multiple 
pharmacological studies have shown that accumulation of M3G and M6G already occurs in 
mild renal impairment (11-13). For this reason, the Dutch guideline for the diagnosis and 
treatment of pain in cancer patients advises to better refrain from prescribing morphine in 
patients with an estimated glomerular filtration rate (eGFR) of <50 ml/min (14). This threshold 
of <50ml/min means that, even in healthy subjects, accumulation of active morphine 
metabolites starts to be relevant at the age of 70 due to an age-dependent decline of renal 
function (15). Physiological changes in terminally ill patients contribute to an almost 
inevitable relevance of this phenomenon in the terminal phase of life: a recent study of the 
pharmacokinetics of morphine, M3G and M6G in terminal ill patients has shown 
accumulation of these metabolites due to a decline in renal function (12). 
 
M6G contributes to an important extent to the analgesic properties of morphine (16-18). 
M3G, on the contrary, is considered to play no role or even an antagonistic role in analgesia 
and is associated with neurotoxic adverse effects like hyperalgesia, allodynia, myoclonus, 
insults and delirium in animal studies and case reports (19-24). Accumulation of M3G in a 
dying patient due to a decline in renal function could therefore lead to undesirable adverse 
effects in this last phase of life. This neurotoxic effects of M3G seem to be enhanced by 
midazolam, a frequently used co-drug in the last phase of life (20). 
 
Alternative opioids 
Oxycodone, fentanyl, buprenorphine hydromorphone and methadone are commonly used 
alternative opioids for the treatment of pain. Only fentanyl and methadone don’t have any 
known active renally cleared metabolites. It is recommended that only experienced 
physicians prescribe methadone, due to its high risk of cumulation as a result of its long and 
individually variable half-life. A risk of cumulation is also known for repeatedly parenteral 
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reabsorption from other tissues because of its strong lipophilicity (25, 26). This makes both 
opioids less suitable as the opioid of first choice for CSCI. 
 
Out of the remaining opioids oxycodone has the best characteristics to be used as the opioid 
of first choice for CSCI instead of morphine: the dosage for parenteral administration is the 
same as for morphine, in contrast to hydromorphone and buprenorphine (14). Costs are also 
barely different between parenteral oxycodone and morphine (27). Yet, in contrast to 
morphine, the central effects of circulating oxidative and reductive metabolites of oxycodone 
in humans are negligible (28). On theoretical considerations it is therefore hypothesized that 
oxycodone might be preferable over morphine for CSCI in terminal patients with a diminished 
renal function in order to reduce the risk of neurotoxic adverse effects. There is a striking lack 
of studies of sufficient quality investigating the clinical effect of this hypothesis. This lack of 
high quality evidence limits structural implementation in daily practice: the current relevant 
guidelines refrain from recommendations regarding oxycodone in renal impairment. 
 
Delirium 
Delirium is a common symptom in the last phase of life: it is estimated that up to 90% of 
patients in palliative care will develop a delirium at some point (29-31). Delirium is associated 
with high levels of distress for both patients, relatives and caregivers (32). As an ultimate 
consequence this could lead to the unwanted situation of a prematurely initiated palliative 
sedation, a process described as ‘the destructive triangle’ (33). The causes for delirium are 
multifactorial. Drugs in general are the main precipitating factor in the development of 
delirium in patients with advanced cancer (34). Opioids are considered to be one of the main 
groups of drugs that might play a contributing role in the development of delirium in patients 
with advanced cancer (35). A rational choice of opioids, aimed at reducing the risk of 
development of delirium, can therefore make an important contribution to the quality of this 
very last phase of life. 
 
Recognition of pain and allodynia/hyperalgesia 
Determining the presence of pain in dying patients could be complicated by reduced 
cognitive and communicative functions in the last days of life. 68-83% of the patients in this 
phase of life experience a decline in cognitive functions and 90-98% is not able to respond 
adequately anymore (36-40). It is probably even more difficult to recognize phenomena like 
allodynia (a pain response from a stimulus that does not normally provoke pain) or 
hyperalgesia ( 
) in this phase of life. It is therefore quite conceivable that in daily practice 
these symptoms are often misinterpreted as an increase in (nociceptive) pain. This could 
lead to dose escalation of the opioid in an attempt to control the assumed pain. In case of 

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morphine this dose escalation could subsequently result in aggravation of the painful 
sensation of allodynia/hyperalgesia due to further accumulation of M3G. Since allodynia and 
hyperalgesia are so difficult to recognize in the last days of life, there is much to be gained if 
the risk of occurrence of these two phenomena could be reduced by a rational choice of 
opioids. 
 
Knowledge among Dutch physicians 
Despite the negative recommendations in guidelines, widespread persistent prescription of 
morphine is still common practice nowadays: Masman et al. showed in 2015 that the vast 
majority (86,6%) of patients in a palliative care setting received morphine at the time of death 
(9). 
 
Rurup et al. noted in 2010 that half of the Dutch physicians are not aware of increased 
plasma concentrations of morphine(-metabolites) in reduced renal functioning and that there 
was a demand for additional education on this subject among 83% of the physicians (41).  
 
Because of the lack of studies of sufficient methodological quality that investigate possible 
differences in the neurotoxic adverse effects delirium and allodynia/hyperalgesia between 
CSCI with morphine and oxycodone for the treatment of pain in dying patients with 
diminished renal function, recommendations regarding preferences for a specific opioid can’t 
be made at the moment. It is therefore not possible to fulfill this need for knowledge and 
training among physicians without further research. 
 
 

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2. OBJECTIVES 
 
The objective of this study is to investigate whether and to what extent the occurrence of the 
neurotoxic adverse effects delirium and allodynia/hyperalgesia differs between morphine and 
oxycodone, administered by continuous subcutaneous infusion (CSCI), for the treatment of 
pain in dying patients with a diminished renal function. 
 
Primary Objective 
To compare the prevalence of delirium between oxycodone and morphine, administered by 
CSCI, for the treatment of pain in dying patients with a diminished renal function. 
 
Secondary Objective 
To compare the prevalence of allodynia/hyperalgesia between oxycodone and morphine, 
administered by CSCI, for the treatment of pain in dying patients with a diminished renal 
function. 
 
Hypothesis 
CSCI of oxycodone for treatment of pain in dying patients with a diminished renal function 
results in a reduced occurrence of the neurotoxic adverse effects delirium and 
allodynia/hyperalgesia in comparison to morphine.  

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3. STUDY DESIGN 
 
This intervention study is designed as a randomized, controlled, observer blinded, 
multicenter, superiority trial (RCT) with two parallel groups with an 1:1-allocation-ratio. 
Patients with a diminished renal function, for this study defined as an eGFR of <50 
ml/min/1.73m², who are eligible for continuous subcutaneous infusion (CSCI) of opioids for 
treatment of pain, are being randomized between morphine and oxycodone. 
 
A double blinded study design is not feasible for budgetary reasons. This study is mainly 
funded by the ZonMw-program ‘Palliantie – Meer dan zorg’. The costs involved in production, 
transportation and application of blinded study medication in accordance with all regulations, 
would result in exceeding the maximum budget allowed by this program. However, we think 
the probability of bias is low, as both treatment arms are active treatments, and none is 
clearly favored over the other with respect to analgesic properties and known side effects. 
Our hypothesis that oxycodone might be preferable over morphine to reduce the risk of 
delirium and/or allodynia/hyperalgesia is solely based on theoretical considerations. To date 
there is no clinical evidence of sufficient quality to accept or reject this hypothesis. It is 
therefore unlike for a patient to present symptoms biased by the knowledge of his allocation 
to any particular study arm. In addition, the highly prevalent cognitive decline in the terminal 
phase of life makes it even more unlike for a patient to be aware of – and thereby biased by 
– a possible theoretical difference in adverse effects of the assigned opioid. 
 
When the treating physician expects that start of CSCI of an opioid for treatment of pain in a 
terminal patient could be a real short-term possibility, he or she will briefly explain the study 
to the patient and/or his or her legal representative and hand out the patient information 
sheet. An appointment with the researcher will be made for the same or the next day via a 
special phone number. The study will be explained verbally, either on site or by telephone, 
and any questions will be answered. After informed consent has been obtained from the 
patient or his/her legal representative randomization will be performed and CSCI with the 
corresponding opioid is initiated by the treating physician. 
 
A delay in onset of treatment of pain should be avoided at any time. In case there is a need 
to start CSCI of an opioid immediately, participation is still possible if the participant or its 
legal representative is willing to provide written informed consent after explanation by the 
treating physician without an appointment with the researcher. 
 
 

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Outcome measures will be gathered by the research assistant 3 times a week until death of 
the participant. A venipuncture for the purpose of the determining the actual eGFR at 
baseline is performed at the first visit of the research assistant. 
 
All deviations from the protocol will be documented. 
 
Duration 
The total time of follow-up is until death. The total duration of the study is 3 years. 
 
Setting 
Participating centers are nursing homes and hospices. 
 

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4. STUDY POPULATION 
4.1 Population (base)  
The study will be conducted in hospices and both somatic and psychogeriatric (PG) wards 
of nursing homes in Limburg, the southern part of the Netherlands. 15 nursing homes and 
1 hospice are participating. The total number of beds in these locations is around 875 
(350 somatic beds, 519 PG beds and 6 hospice beds), dived over 54 wards (24 somatic 
wards, 29 PG wards, 1 hospice). All of the participating locations are part of Envida, a 
health care organization in the region.  
 
Both somatic and PG wards of nursing homes are included in this study, because CSCI 
with either morphine or oxycodone is already a common treatment in regular care for both 
patients with and without dementia (42-44). Inclusion of both patient groups would 
therefore best represent daily practice and optimizes applicability of the results. Special 
attention will be paid to the aspect of objection or resistance in the group of incapacitated 
patients, as further described in chapter 11.3.  
 
Medical care in these nursing homes and hospices is provided by a permanent team of 
specialized physicians, employed by Envida. This allows for maximum adherence to the 
research protocol, because we are not dependent on varying external care providers, who 
might not be aware of the ongoing study, for the evening, night and weekend shifts.  
 
Two other organizations, similar to Envida in size and population, intend to participate in 
this study at a later stage. 
 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
- minimal age of 18 years at the time of inclusion; 
- the subject is in the terminal phase, i.e. death in the near future is expected by the 
treating physician; 
- start of CSCI with an opioid for treatment of pain is indicated by the treating physician; 
- willingness to allow one-time blood collection for assessment of renal function (eGFR); 
- a signed informed consent is given by the participant or his/her legal representative. 
 

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4.3 Exclusion criteria 
Anyone who meets any of the following criteria will be excluded from participation in this 
study: 
 
- delirium at the time of inclusion; 
- opioid induced hyperalgesia (OIH) at the time of inclusion; 
- a medical necessity to apply a different opioid than morphine or oxycodone, such as 
previously demonstrated non-response to morphine or oxycodone (defined as a complete 
absence of any pain reduction after appropriate dosage), previously demonstrated 
unacceptable side effects of morphine or oxycodone, or a medical indication for an opioid 
with NMDA-receptor-antagonistic properties (currently only known for methadone); 
- a documented allergy for morphine or oxycodone. 
 
Subjects with an eGFR >50 ml/min/1.73m2 should not be included in the study, because 
accumulation of metabolites is considered to be irrelevant in this range of renal functions. 
Despite this fact, we cannot formulate an unaffected renal function as an exclusion 
criterion prior to allocation, because the time needed for assessment of the renal function 
could lead to either an unethical delay in treatment of pain or occurrence of death even 
before the lab results are known. Therefore renal function is assessed after inclusion. In 
case a subject turns out to exceed the threshold of 50 ml/min/1.73m2, this will be 
considered as meeting an extended exclusion criterion and the subject concerned will be 
replaced by a new subject.     
 
 
4.4 Sample size calculation 
Sample size calculation is performed for the primary objective, i.e. the comparison of the 
percentage of patients who develop delirium in the period between start of CSCI with 
oxycodone (intervention group) or morphine (control group) and death. Although we 
expect the intervention group to perform superior to the control group in this respect, this 
hypothesis is purely based on theoretical considerations. No former (clinical) studies of 
sufficient quality exist to rule out the possibility that the intervention group actually turns 
out to perform inferior to the control group. Therefore sample size calculation is based on 
a two-tailed test. Based on the available literature, the percentage of delirium in terminal 
patients is estimated at 86% (29, 30, 45). A difference of 15% is considered to be clinically 
relevant. The probability of a type 1 error is fixed at 5%. Groups are analyzed according to 

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the intention to treat principle. In order to achieve a power of 80% for detecting a clinically 
relevant difference, 117 patients per group are needed. 
 
In order to assess feasibility, we counted the number of terminal patients with CSCI of 
opioids in the daily medical reports for evening-, night- and weekend shifts of physicians 
of Envida for 3 months in 2016. Extrapolation of these results lead to a number of 120-150 
terminal patients with CSCI of opioids within Envida in 1 year. In addition, we searched 
the electronic medication prescription system of Envida for prescriptions of CSCI of 
opioids in deceased patients for 5 months in 2017. This search resulted in 52 patients with 
CSCI of an opioid for this period, which can be extrapolated to 125 patients per year. 
 
Both of these two separate observations resulted in approximately 120 patients with CSCI 
of an opioid per year per organization. For the intended 2-year inclusion period within 3 
(comparable) organizations, this would result in an estimated total of 720 eligible patients. 
In order to achieve the required number of participants 32,5% of the eligible patients 
should be willing to participate in our study. This study was presented to the members of 
the central client council of Envida, who are representative for the intended study 
population. The expectation of this council was that the willingness to participate would by 
high. 
 
An exact estimation of the number of subjects that have to be replaced after inclusion due 
to an eGFR >50 ml/min/1,73m2 is not possible, because these data do not exist for our 
study population. A recent study showed that about half of the study’s participants 
developed an eGFR <60ml/min/1,73m2 by the time they reached the terminal phase of life 
(46). Based on this study’s findings we make a rough estimate that 117 would meet the 
extended exclusioncriterion of an eGFR <50ml/min/1,73m2. However, compared to our 
study population of mainly frail elderly, the population in this study was younger, had less 
comorbidity and had a lower percentage of subjects that had pre-existing kidney disease 
(14% vs. 26%). Combined with the clinical experience of elderly care physicians of a rapid 
decline in renal function during episodes of intercurrent illness in this frail population, it is 
thought to be safe to assume that the number of eligible subjects provides sufficient 
reserve to replace participants with an eGFR >50 ml/min/1.73m2. Despite this clinical 
experiences that would indicate a lower number of included subjects, we have to make a 
larger estimate of a total of 351 included participants, based on the limited available 
evidence. 
 
 

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5. TREATMENT OF SUBJECTS 
 
5.1 Investigational product/treatment 
The investigational products are oxycodone and morphine. After inclusion a participant will 
start with continuous subcutaneous infusion (CSCI) of either oxycodone or morphine as 
determined by randomization. Both continuous administration by a syringe driver as well 
as bolus administration every 4 hours will be regarded as CSCI.  
 
 
5.2 Use of co-intervention 
In both groups all pharmacological and non-pharmacological co-interventions for 
treatment of any occurring symptoms are allowed. All participating physicians are advised 
to apply these co-interventions in accordance with the ‘Pallialine-guidelines’, i.e. the Dutch 
palliative guidelines, provided by the IKNL (47). All pharmacological co-interventions will 
be registered. 
 
Palliative sedation as a co-intervention is allowed when all requirements of the guideline 
‘Palliatieve sedatie’ of the KNMG are met (48).  
 
 
5.3 Escape medication 
Escape medication for breakthrough pain can be applied in accordance with the Dutch 
2016 guideline ‘diagnostiek en behandeling van pijn bij patiënten met kanker’ (14): 
- 
a Rapid-Onset Opioid (ROO), i.e. transmucosal or intranasal administered 
formulations of fentanyl; or: 
- 
a subcutaneous bolus injection of the same opioid as administered by CSCI in a 
dosage of 10-15% of the 24-hour CSCI-dosage, up to a maximum amount of 6 
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6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational product(s) 
Oxycodone Hydrochloride Solution for Injection or Infusion: 
An opioid agonist, regular on the market in the Netherlands and known in Dutch as 
‘oxycodon injectievloeistof’ or ‘OxyNorm® injectievloeistof’. 
 
Morphine Hydrochloride Solution for Injection or Infusion: 
An opioid agonist, regular on the market in the Netherlands and known in Dutch as 
‘morfine injectievloeistof’. 
 
 
6.2 Summary of findings from non-clinical studies 
We refer to the Summary of Product Characteristics (SPC) of both products. 
 
 
6.3 Summary of findings from clinical studies 
In a recent systematic review regarding the use of opioids in cancer patients with renal 
impairment only 15 studies were identified: 8 prospective observational and 7 
retrospective studies, all of which were judged of low quality. Morphine was by far the 
most investigated opioid. Indications that morphine metabolites play a role in causing 
adverse effects in renal impairment were inconsistent (49). 
 
A more recent cross-sectional multicentre study comparing the side effects of morphine, 
fentanyl and oxycodone in 1147 cancer patients found that patients with higher M3G 
serum concentrations were more likely to have severe cognitive dysfunction than patients 
with lower M3G serum concentrations (OR: 1.63; 95% CI: 1.03-2.56; p=0.04), whereas 
patients with higher oxycodone serum concentrations were only more likely to report 
severe fatigue (OR: 1.70; 95% CI: 1.04-2.78; p=0.03) than patients with lower oxycodone 
serum concentrations. It didn’t show any association between renal function and 
differences between opioids in cognitive functioning or pain. However, the applied 
measuring instrument (EORTC QLQ-C30) does not determine presence of delirium or 
allodynia/hyperalgesia (50). 
 
 

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6.4 Summary of known and potential risks and benefits 
Both morphine and oxycodone are strong opioids with well-documented analgesic 
abilities. Both share the side effect profile of strong opioids: constipation, sedation, 
nausea, vomiting, dizziness, hypotension. Both investigation products in this study are 
used within the registered indications. 
 
 
6.5 Description and justification of route of administration and dosage 
The two investigated products, morphine and oxycodone, are both registered products for 
continuous subcutaneous infusion, as described in the ‘KNMP Kennisbank’ as well as in 
the IKNL-guideline ‘Pain’ (51-53). Widespread use of both of these opioids as well as the 
continuous subcutaneous route of administration are an essential part of common practice 
in treatment of pain in terminally ill patients.  
 
 
6.6 Dosages, dosage modifications and method of administration 
All participating physicians are asked to perform dosage and dosage modifications in 
accordance with the Dutch 2016 guideline ‘diagnostiek en behandeling van pijn bij 
patiënten met kanker’ (14). The medication lists collected by the research assisted in 
sealed envelopes at each visit, are analysed by the researcher for indications of 
deviations from this directive on dosage. In case a deviation is suspected, it will be 
recorded and further investigated by the researcher. 
 
 
6.7 Preparation and labelling of Investigational Medicinal Product 
After randomization the treating physician will initiate CSCI with the assigned opioid by 
following the regular local procedures and protocols, applicable to the institution where he 
or she is employed, for prescription, distribution and administration of medication. 
 
 
6.8 Drug accountability 
The regular local procedures and protocols of the individual institutions, all of which 
comply with the Dutch Opium Act, apply. 

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable. 

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8. METHODS 
8.1 Study parameters/endpoints 
The objective of this study is to determine whether there are any relevant differences in 
the occurrence of the neurotoxic side effects delirium and allodynia/hyperalgesia between 
the intervention group receiving oxycodone and the control group receiving morphine. All 
parameters will be assessed three times a week by a trained research assistant, who will 
be blinded for the assigned opioid until death of the participant. 
 
8.1.1 Main study parameter/endpoint 
The occurrence of the neurotoxic adverse effect delirium at any time between start 
of CSCI with the opioid and death. 
 
The Delirium Observation Screening (DOS)-scale is scored by the nursing staff on a 
daily basis and collected 3 times a week by the research assistant to screen for 
presence of delirium (54). In case this screening instrument indicates a possible 
presence of delirium, the researcher will ask the treating physician to confirm or 
reject the clinical diagnosis of delirium in accordance with the DSM-IV-TR criteria 
(55).  
 
8.1.2 Secondary study parameters/endpoints 
The occurrence of the neurotoxic adverse effect allodynia/hyperalgesia at any time 
between start of CSCI with the opioid and death. 
 
Presence of allodynia or hyperalgesia is assessed by a trained research assistant 
by asking the subject whether respectively lightly brushing with a piece of cotton 
wool on the skin or performing pin-prick testing provokes pain or aggravates already 
existing pain (56, 57). In case the subject is not able to adequately respond verbally 
the items of the Rotterdam Elderly Pain Observation Scale (REPOS) are used to 
determine presence of a painful response (58, 59). 
 
 
 

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8.1.3 Other study parameters 
The following baseline characteristics will be recorded at the time of a participant’s 
inclusion: 
- Age 
- Gender 
- Stay in hospice or at somatic or psychogeriatric nursing home ward 
- Medication use prior to start of CSCI 
- Creatinine (by one time blood collection) and calculated eGFR (by use of the CKD-
 EPI-formula) 
- Main diagnosis and co-morbidities 
 
The following other data will be recorded: 
- time between start of CSCI with oxycodone or morphine and death 
- pain scores (NRS or REPOS) prior to testing at each visit of the research assistant 
- current medication use at each visit of the research assistant 
- reported side effects as observed by the nursing staff 
- quality of death, perceived by relatives. 
 
A detailed description of the procedures used to determine the study parameters is 
provided in chapter 8.3. 
 
 
8.2 Randomisation, blinding and treatment allocation 
Randomization is performed by the web based randomization program ALEA, hosted by 
the CTCM. In order to prevent an uneven distribution of relevant prognostic factors, 
allocation will be stratified by means of minimisation for type of ward (somatic or 
psychogeriatric, representing absence or presence of a clinical relevant stage of 
dementia and thereby indirectly also status of mental and communicative capabilities), for 
presence or absence of opioid use at baseline and age. It is not possible to perform 
stratification for the level of renal impairment, since it is not possible to determine the 
renal function prior to randomisation (for afore mentioned reasons). In case this might 
result in any imbalance between the study arms, the differences will be compensated for 
in statistical analysis.  
 
When a patient is eligible for inclusion the treating physician will contact the research-
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consent, the researcher will perform randomization by accessing ALEA. The treating 
physician is subsequently informed of the opioid assigned by this randomization 
procedure. The phone number for randomization is available 24/7 in order to prevent any 
delay in onset of treatment of pain. 
 
The trained research assistant, who will measure the participant’s outcome parameters 
on location, will only be provided with personal and location data needed to visit and 
identify the participant by the researcher. The research assistant does not receive any 
information regarding the assigned opioid. 
 
 
8.3 Study procedures 
After inclusion and allocation to either morphine or oxycodone participants will be visited 
by the research assistant three times a week until death. During this period of follow up all 
participants will undergo the following procedures to determine the predefined research 
parameters (see also figure 1 for a flow-chart of the study procedures and table 1 for a 
description of the individual procedures):  
 
At the first visit after inclusion a one-time venipuncture will be performed to collect blood to 
determine the creatinine level in laboratory testing performed by the Central Diagnostic 
Laboratory of the Maastricht University Medical Centre. This result is used to calculate the 
eGFR at baseline by using the CKD-EPI-formula. In case a participant has no diminished 
renal functining, defined as an eGFR <50 ml/min/1.73m², he or she will be withdrawn from 
the study and consequently excluded from data collection. These withdrawn subjects will 
be replaced by new subjects in order to achieve the required sample size. 
 
All other procedures will be performed at each visit of the research assistant. 
 
Two weeks after a participant’s death, and only when a participant or his legal 
representative has given permission in the written informed consent, a significant other or 
legal representative will be contacted by telephone by the researcher to ask whether he or 
she is willing to participate in an interview in which the perceived quality of dying is 
assessed by using the Quality of Dying and Death (QoDD) Questionnaire. 
 
 

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Figure 1: Flow chart of study procedures 
 
 
Depending on the ability of the subject to adequately respond verbally either the 0-10 
Numeric Rating Scale (NRS) or the Rotterdam Elderly Pain Observation Scale (REPOS) 
will be used to assess pain prior to testing. Subsequently the NRS or REPOS will be 
scored again while performing brushing with cotton wool and pin-prick testing to assess 
for presence of allodynia and hyperalgesia respectively. 
 
Delirium Observation Screening (DOS)-scores, assessed by the nursing staff three times 
a day, are collected by the research assistant and analysed by the researcher. In case the 
mean daily DOS-score exceeds the cut-off point of 3 points, the suspected diagnosis of 
delirium needs to be confirmed or rejected by a clinician. The DOS is an easy to use 
nurse-based observation instrument without the need for prior training. Despite the 
nursing staff not being blinded for the assigned opioid, the risk of missing delirious 
subjects during this screening is negligible, because of its negative predictive value close 
to 100% (60-62). In order to perform a blinded confirmation or rejection of the final 
diagnosis after this screening, this procedure will be performed by a psychologist, who is 
not aware of subjects’ medication use. Availability of a psychologist on each ward is part 
of the regular care in Dutch nursing home settings. 
 

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The research assistant will also collect sealed envelopes with a copy or print of the 
medication list of each participant at each visit. These envelopes are sealed to guarantee 
blinding of the research assistant. The collected medication lists are assessed by the 
researcher for: 
- use of co-medication for treatment of delirium; 
- use of co-medication for treatment of allodynia/hyperalgesia; 
- use of sedatives for palliative sedation; 
- use of co-medication that might provoke delirium; 
- adherence to the protocol for opioid dosage. 
 
 
Table 1: Description of study procedures 
 
Procedure 
Parameter 
Description 
Invasive 
procedures 
Venipuncture 
eGFR1) 
One-time blood collection for laboratory assessment of the 
renal function (eGFR) at the first visit of the research 
assistant, who is qualified and competent to perform this 
procedure. Blood samples will be transported to the 
laboratory in a transportation box meeting UN3373/P650-
specification in accordance to the ADR regulations. 
Laboratory 
test 
Creatinine 
eGFR1) 
This laboratory test is performed from the collected blood 
sample by the Central Diagnostic Laboratory of the 
Maastricht University Medical Centre in order to calculate 
the eGFR at baseline by using the CKD-EPI-formula (63). 
Physical examination 
Touching and 
lightly 
brushing with 
a piece of 
cotton wool 
Allodynia2) 
This procedure is performed 3 times a week on both arms 
and legs by the research assistant. A painful sensation or 
an increase in pain as a result of the procedure is 
indicative for the presence of allodynia (56, 57). 
Pin-prick 
testing 
Hyper-
algesia3) 
This test is performed 3 times a week by the research 
assistant. A standardized method is used by putting a free 
floating 23G needle in a 2 ml syringe with the plunger 
removed perpendicular to the skin. This procedure is 
performed on both arms and legs. A painful sensation or 
an increase in pain as a result of the procedure is 
indicative for the presence of hyperalgesia (56, 57). 
Table continues on the next page 

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Questionnaires 
Delirium 
Observation 
Screening 
(DOS) 
Delirium 
This observational screening instrument for delirium is 
completed on a daily basis by the nursing staff. The 
results are collected three times a week by the research 
assistant. In case a DOS-score exceeds the cut-off point 
of 3 points a notification will be send by the researcher to 
the ward’s psychologist and he or she will be asked to 
confirm or reject the clinical diagnosis of delirium (54). 
0-10 Numeric 
Rating Scale 
(NRS) 
Pain prior 
to testing 
The NRS is used to quantify the level of pain experienced 
by a subject who is able to respond verbally (64). 
Rotterdam 
Elderly Pain 
Observation 
Scale 
(REPOS) 
Pain prior 
to testing, 
allodynia2) 
and hyper-
algesia3) 
In case a participant is no longer able to adequately 
verbally report presence or absence of pain the items of 
this observatory instrument are used by the research 
assistant to determine the presence of pain prior to testing 
and to objectify the physical reactions to the brushing with 
a piece of cotton wool and the pin-prick test, which will 
evoke a sensation of pain when allodynia/hyperalgesia is 
present. The REPOS, originally designed to detect pain in 
non-communicative and cognitively impaired nursing 
home residents, has recently also been validated for 
detection of pain in non-communicative terminal patients 
(58, 59). 
Quality of 
Dying and 
Death (QoDD) 
Quality of 
dying, as 
percveived 
by relatives 
Quality of dying, as perceived by relatives, is assessed by 
the researcher two weeks after a participant’s death in an 
interview. This interview only takes place when both 
written informed consent is given by the participant, and 
the relative is willing to participate (65).  
1), 2), 3): procedures with corresponding numbers are used in conjunction for determination of the 
mentioned parameter 
 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time if they wish to do so, without the need to provide 
any reason and without any consequences.  
 
8.4.1 Specific criteria for withdrawal 
A subject will be withdrawn by the researcher in case the eGFR at baseline, as 
determined from the blood collected by venipuncture at the first visit after 
randomization, turns out to be >50 ml/min/1.73m². This is considered as an 
extended exclusion criterion. 

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Participants will be withdrawn by the researcher or the treating physician in case of 
any of the following conditions: 
- the condition of the participant has changed in such a way that there is no longer a 
medical indication for administration of opioids; 
- the assigned opioid leads to side effects that are perceived as unacceptable by the 
individual participant (for example persistent nausea, pruritus or drowsiness); 
- there is a medical need to rotate to a different opioid than assigned; 
- continuation of CSCI is impossible due to patient related, situational, mechanical or 
practical reasons or circumstances; 
- a participant is transferred to a non-participating institution. 
 
 
8.5 Replacement of individual subjects after withdrawal 
Only in case of withdrawal as a result of meeting the extended exclusion criterion, i.e. an 
eGFR >50ml/min/m2, participants will be replaced. In all other cases participants will not 
be replaced after withdrawal from the study, in accordance with the intention-to-treat 
principle. 
 
 
8.6 Follow-up of subjects withdrawn from treatment 
In case a participant wants or needs to be withdrawn from the study treatment, he or she 
will be asked for permission for continuation of follow-up to allow full intention-to-treat 
analysis. 
 
 
8.7 Premature termination of the study 
The study will immediately be terminated prematurely when interim analysis shows signs 
of serious disadvantage for the participants in one of the groups in comparison to the 
other group. In case this situation occurs, the researcher will ensure that the METC, all 
participants and all participating institutions are informed. From that moment on the 
treating physician of each individual participant will determine which opioid is most 
suitable for continuation of the treatment of pain according to existing guidelines. 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to administration of morphine or 
oxycodone. All adverse events reported spontaneously by the subject or observed by 
the investigator or his staff will be recorded. Known side effects, as registered in 
‘Kennisbank KNMP’, are not considered as AEs. 
 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event (SAE) is any untoward medical occurrence or effect that:  
- 
results in death within 120 minutes after start or increase of dosage of CSCI of 
morphine or oxycodone (explained in more detail below); or 
- 
requires hospitalisation; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
 
Death as a SAE in terminally ill patients 
Since participants are terminally ill patients, death is an inevitable event as a result of 
the ongoing dying process caused by the underlying terminal disease. The end point 
of follow-up is defined as the moment of death. So death is to be expected for every 
subject. The vast majority of deaths are therefore not to be regarded as SAEs. 
 

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Available evidence focusing on the relationship between administration of opioids and 
death in the study population, i.e. terminally ill patients with pain, suggest that it is 
unlikely that death of a subject in this very specific population is related to the 
administration of an opioid: although opioids can cause respiratory depression in 
healthy volunteers without pain, multiple studies have shown that clinically relevant 
respiratory depression does not occur when opioids are titrated against pain (66-70). 
Considering assumed concerns about potential life-shortening effects of opioids from 
a broader perspective than only by means of respiratory depression, studies focusing 
on survival in relation to opioid use and dosage not only confirm that survival is not 
affected negatively when titrated against symptoms, but even suggest a possible 
association with an prolonged life-expectancy, especially at higher dosages (3, 71-
75).  
 
Although theoretically unlikely, as explained in the previous section, we consider the 
possibility of a contribution of the investigated product to occurrence of death when a 
time-dependent relationship exists between death and administration of the product. 
Available pharmacokinetic data in this respect are limited to: 
- Tmax of rectally administered morphine: 45-60 minutes (52); 
- Tmax of orally administered oxycodone: 90 minutes (53); 
- time to maximal analgesia of subcutaneous administered morphine: 50-90 minutes 
(52).  
 
A causal relationship between administration of morphine or oxycodone and death is 
more plausible when death occurs within the timeframe of reaching Cmax and/or 
maximum therapeutic effect. Based on the pharmacokinetic data mentioned above, 
with some margin added, death is only considered as a SAE when it occurs within the 
first 120 minutes after start or increase of dosage of CSCI of the opioid. 
 
Handling of SAEs 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events. 
 
The sponsor will report the SAEs through the web portal ‘ToetsingOnline’ to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 

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period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in the Summary of Product Characteristics (SPC) for an authorised 
medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
‘ToetsingOnline’ to the METC : 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal ‘Eudravigilance’ or 
‘ToetsingOnline’ is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 

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be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
 
Breaking the code for SUSAR reporting 
The study design is observer blinded. The randomly assigned opioid is prescribed  
by the treating physician and supplied according to local procedures. Medical care is 
provided by a permanent team of physicians with uniform medical records. In case 
of a medical emergency the treating medical team is therefore always aware of the 
assigned opioid and the research assistant does not need to be unblinded. 
Consequently a specific procedure for breaking the code in case of an emergency is 
not necessary. 
 
For SUSAR reporting the following procedure has to be followed: 
1. A copy of the medication list or a printout of the electronic medication 
prescription system is made by the treating physician. 
2. This copy or printout is placed inside a non-transparent envelope. 
3. The envelope is sealed and a signature is put over the envelope flap to ensure 
that the seal can’t be broken unnoticed. 
4. The date, time and location of sealing are noted on the envelope, as well as the 
name of the person performing the sealing. 
5. The sealed envelope is collected by the research assistant, CI or PI. 
6. Only the CI and PI are allowed to break the seal and open the envelope. Before 
opening the envelope they should ensure themselves that no other, 
unauthorized persons can see the contents. 
7. The CI/PI opening the envelope keeps a code breaking log, that registers: 
a. patient trial number; 
b. reason for breaking the code (in this case: SUSAR reporting); 
c. name of the person requesting the code break; 
d. date, time and location of sealing the envelope, as noted on the 
envelope; 
e. name of the person sealing the envelope, as noted on the envelope; 
f. date, time and location of breaking the seal and opening the envelope; 
g. name of the CI/PI breaking the seal and opening the envelope; 
h. signature of the CI/PI breaking the seal and opening the envelop. 
 

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By using the participant’s actual medication list instead of only the randomization 
outcome the CI/PI can also check for prescription or dosing errors of the assigned 
opioid in SUSAR reporting. 
 
 
9.3 Annual safety report 
 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol.  
 
 
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
Not applicable. 
 

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10. STATISTICAL ANALYSIS 
A table with baseline characteristics will be provided for both groups. We will assess 
these baseline characteristics for any imbalance between both study arms. In case any 
imbalance exists, we will consider whether this is a potentially clinically relevant 
confounder. When considered clinical relevant, we will correct for this imbalance in 
statistical analysis. Randomization is stratified for what we consider to be the main 
potentially clinically relevant confounders, i.e. ‘stay on a psychogeriatric ward’, ‘former 
use of opioids’ and age. We do therefore not expect any imbalance in this regard. 
However, since renal function can only be assessed after allocation, stratification can’t be 
performed for stage of renal impairment, i.e. moderate (eGFR 30-50 ml/min/1.73m2), 
severe (eGFR 15-29 ml/min/1.73m2) or endstage (eGFR <15 ml/min/1.73m2). It is 
therefore not unlikely that any imbalance could arise in the distribution of the various 
stages of renal impairment.  As the degree of accumulation of metabolites is related to 
the degree of renal impairment, we consider this imbalance to be the most important 
confounder that needs to be corrected for. 
 
All analyses will be performed according to the intention-to-treat principle. The risk of a 
degree of cross-over after allocation to the extent that it might affect outcome parameters, 
is considered low for the same reasons that it is thought to be unlikely for subjects to be 
biased by the knowledge of the assigned opioid, as explained in the study design 
(chapter 3), i.e. no known difference in side effects between the two opioids and a highly 
prevalent cognitive decline in the terminal phase of life. In addition, in daily practice 
switching of opioids barely occurs in this phase of life due to the limited time between 
start of CSCI with an opioid and death. 
 
Imputation techniques will be used for supplementation of incomplete data, thereby 
guarantying analysis of all participants in the group they were assigned to by 
randomization. The method we will use will depend on the proportion of missing values 
and on the assumptions that can be made about the missingness mechanism after 
collection of the data: In case the percentage of incomplete cases is less than, or equal 
to, 5%, we will use single stochastic imputation to impute the dataset, as the difference in 
precision due to not taking between-imputation variance into account is likely to be 
negligible. If the proportion of incomplete records exceeds 5%, multiple imputation will be 
used. In that case, the number of imputations will be set to 10. For both imputation 
strategies, the imputed values will be drawn using predictive mean matching with a fully 
conditionally specified model. If, after collection of the data, we expect that data are 
missing not at random, we will impute using a missing not at random mechanism (again, 

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using single or multiple imputation), and perform a sensitivity analysis to see whether our 
conclusions are robust. 
 
10.1 Primary study parameter(s) 
Pearson’s Chi-squared test will be used to assess whether there is any distinction 
between both groups in the proportion of patients in whom delirium has occurred. In case 
the analysis of the baseline characteristics showed any clinically relevant imbalance, we 
will also perform a multivariable logistic regression analysis in order to correct for this 
imbalance. 
 
 
10.2 Secondary study parameter(s)  
Depending on the level of measurement a Chi-squared test or a T-test will be used to 
assess differences in secondary study parameters, and logistic and linear regression for 
baseline-corrected estimates. 
 
 
10.3 Interim analysis 
An interim analysis is performed at a predefined clinically relevant moment in order to 
determine whether continuation of the study is considered safe for the study’s 
participants. The moment of interim analysis and the criterion for safety have been 
determined by means of clinical expert consensus. 
 
This interim analysis will be performed for the primary and secondary study parameters 
after the end of follow up, i.e. death, of the first 30 participants in each group. 
 
A difference between the intervention and control group of more than 50% for the primary 
study parameter is considered to be an indication that one of the groups is significantly 
harmed more than the other. When this difference can’t be contributed to other factors, 
like an uneven distribution of baseline characteristics, especially other medication use, it 
is considered unethical to withhold one of the groups from the superiority of one of the 
opioids. Therefore, this potential situation is regarded as a stopping rule.    
 
 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the 7th Declaration of Helsinki 
(Fortaleza 2013) and in accordance with the Medical Research Involving Human Subjects 
Act (WMO). 
 
 
11.2 Recruitment and consent 
All patients and/or their legal representatives of participating wards will receive an 
information leaflet, briefly explaining that their ward is participating in the study and that 
they can be asked for their willingness to participate by the time they’ll meet the inclusion 
criteria. 
 
When the treating physician of a patient on a participating ward expects that start of CSCI 
of an opioid for the treatment of pain in a dying patient could become a real short-term 
possibility, he or she will briefly explain the study to the patient and/or his/her legal 
representative and hand out the patient information sheet, which explains the objectives 
and methods of the study in understandable language. The treating physician informs the 
researcher via a special telephone number. The researcher will make an appointment 
with the patient and/or his/her legal representative for the same or the next working day. 
The study will be explained verbally, either on site or by telephone, and questions will be 
answered. Also the opportunity to consult an independent physician is emphasized.  
 
Subjects will only be included in the study after written informed consent is obtained by 
the treating physician. 
 
This study should never lead to a disturbance of usual care. Especially a delay in onset of 
treatment of pain should be avoided at any time. Usually start of CSCI of an opioid is part 
of advance care planning, resulting in enough time for the researcher to contact the 
patient or its legal representative and thereafter for the subjects to consider participation. 
However, since medical conditions in dying patients could become unstable 
unexpectedly, resulting in a rapid deterioration and need to start CSCI of an opioid 
sooner than initially expected, available time for explanation by the researcher and 
subsequent consideration by the subject is variable. In case there is a need to start CSCI 
of an opioid immediately, participation is still possible if the participant or its legal 

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representative is willing to provide written informed consent after explanation by the 
treating physician without an appointment with the researcher. 
 
 
11.3 Objection by incapacitated subjects 
Since the major part of dying patients experiences a decline in cognitive functions and are 
not able to respond adequately anymore, it is essential to include this incapacitated 
population in our study (36-40). When a participant is or has become incapacitated as a 
result of his medical condition or cognitive impairment, his or her legal representative 
decides whether the subject will be participating in the study or not, unless the subject 
previously has stated explicitly otherwise. The Dutch law WGBO determines which 
persons are entitled to act as legal representatives. Signs of consistent objection or 
resistance to any of the study procedures after inclusion, especially the invasive 
procedure (venipuncture), have to be considered as an expression of the participant’s 
wish to not participate in the study any longer. Consequently he or she will be withdrawn 
from the study immediately. In case a incapacitated participant shows signs of objection 
or resistance to the continuous subcutaneous route of administration (for example by 
removal of the infusion tube or needle) the treating physician will decide whether 
continuation of CSCI of an opioid is a medical necessity to avoid severe suffering from 
pain. When there is no medical necessity or when adequate pain control can be achieved 
otherwise, it is not allowed for the subject to participate in the study any longer and 
he/she will be withdrawn from the study according to the criterion ‘continuation of CSCI is 
impossible due to patient related, situational, mechanical or practical reasons or 
circumstances’ as described in section 8.4.1. 
 
 
11.4 Benefits and risks assessment, group relatedness 
Participants assigned to the oxycodone group could potentially benefit from the 
theoretically hypothesized reduced risk of developing delirium and/or 
allodynia/hyperalgesia compared to the morphine group. This potential benefit for the 
oxycodone group is to be regarded with a considerable amount of uncertainty, since no 
former evidence of sufficient quality exist to accept or reject this hypothesis.  
Furthermore, both CSCI with oxycodone and morphine are already established 
treatments for pain in palliative care and part of common medical care in the Netherlands. 
The choice for either one of these opioids is seldom based on patient characteristics, but 
more likely to be determined by personal preferences or experiences of individual 

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physicians or institutions. Therefore potential drug-related benefits or risk, if any would 
exist, do not differ from care as usual. 
 
Potential disadvantages of participation in this study in general could be: 
- possibly experiencing some transient inconvenience from study procedures, such as the 
one-time venipuncture and cotton wool/pin prick test; 
- visits of an unfamiliar person 3 times a week during the last phase of life; 
- loss of time of approximately 5 to 10 minutes per visit; 
- a participant must adhere to the study protocol. 
 
The risk of venipuncture-related complications is considered low, as further explained in 
chapter 13.2. 
 
 
11.5 Compensation for injury 
Envida has a liability insurance which is in accordance with article 7 of the WMO. 
 
The sponsor also has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides coverage for damage to 
research subjects through injury or death caused by the study. The insurance applies to 
the damage that becomes apparent during the study or within 4 years after the end of the 
study. 
 
 
11.6 Incentives 
Not applicable: participants nor participating institutions will receive any kind of 
remuneration or compensation for participation in the study. 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
All data in this study will be handled digitally by use of electronic Case Report Forms 
(eCRF) and the data management system MACRO, both provided and hosted by the 
Clinical Trial Center Maastricht (CTCM). These systems comply with all applicable 
regulations regarding data security. Only authorized personnel will have access to these 
systems. Data storage is secured by the CTCM by regular back-ups. Data will be stored 
for 15 years.  
 
No identifiable reference to subjects will be made in analysis, reports or publications. To 
protect the confidentiality of subjects all data will only be linked to a subjected by an 
numeric identification code, of which the key will be safeguarded by the investigator. 
 
Blood samples for determining the eGFR to decide whether the extended exclusion 
criterion is met, are processed by the Central Diagnostic Laboratory of the Maastricht 
University Medical Centre. This laboratory needs the samples to be identifiable. The 
laboratory results will delivered by SAP, the electronic patient file system of the 
Maastricht University Medical Centre. These results will be entered into the eCRF by the 
researcher and will be linked to a subject by code only from thereon. Blood samples will 
be destroyed by the laboratory after 1 week and will not be used for any other purpose 
than described in this study protocol.  
 
Publication 
Public disclosure and publication of the research data will be according the CCMO 
statement on publication policy 
 
 
12.2 Monitoring and Quality Assurance  
This study will be registered at clinicaltrials.gov. Monitoring will be performed by the 
Clinical Trial Center Maastricht (CTCM), an independent institution which follows the 
international ICH-GCP (Good Clinical Practice) guidelines.  
 
The monitoring plan will at least consist of the following aspects: and at least incorporate 
the following items: 
- Verification of the informed consents, in- and exclusion criteria, reported SAEs and 
SUSARS, and Case Report Forms (CRFs). 

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- Site Initiation Visit (SIV): during the SIV the Trial Master File/Investigator Site File (TMF) 
will be verified. In addition, all aspects of the protocol will be checked, including personnel 
responsibilities. 
- Interim Monitoring Visit (IMV): during the IMV all documentation will be checked and 
CRFs are being verified according to the source documents. 
- Close-Out Visit (COV): during the COV a final verification of the TMF will be performed 
and all outstanding issues will be finalized. 
  
 
12.3 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
 
12.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  

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The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
 
12.6 Public disclosure and publication policy 
Public disclosure and publication of the research data will be performed in accordance to 
the CCMO statement on publication policy. 

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13. STRUCTURED RISK ANALYSIS  
 
13.1 Potential issues of concern 
Since the investigated products are registered products to be used in regular care for the 
registered indication and route of administration, and not in combination with other 
products, and the risk of venipuncture-related complications is considered low, as further 
explained in chapter 13.2, this chapter is not applicable. 
 
 
13.2 Synthesis 
 
Investigational products 
The two investigated products, morphine and oxycodone, are both registered products for 
CSCI, as described in the ‘KNMP Kennisbank’ as well as in the IKNL-guideline ‘Pain’. 
Widespread use of both of these opioids as well as the continuous subcutaneous route of 
administration are an essential part of common practice in treatment of pain in terminally 
ill patients. Since the indication, dosage and use of the products in the study does not 
differ from the registered use in common practice, participants are not exposed to any 
additional medication-related risks. 
 
Venipuncture 
A one-time blood collection by venipuncture is not a common procedure in regular care for 
terminal patients receiving CSCI with morphine or oxycodone for treatment of pain. It 
could therefore pose a potential additional risk to participants. 
 
Potential risks associated with venepuncture are hematoma formation, infection, nerve 
damage, syncope or fainting or excessive bleeding. However, the risk of venipuncture-
related complication is considered very low: a recent study, analysing 1.082.053 
venipunctures in 10 years, showed an incidence rate of 0,0271% for any venipuncture-
related complication and 0,0015% for obvious nerve injuries. No patients exhibited 
persistent severe symptoms (76). These findings are in line with an similar older study 
(77). Higher incidence rates of nerve injuries have been reported for blood donation-
related venipunctures. The incidence rates range from 0,0144% to 0,0158% and therefore 
still imply a low risk (78, 79). 
 
 
 

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