Influence of Δ9-tetrahydrocannabinol (THC) on Oxycodone Induced Ventilatory Depression in Healthy Volunteers
Phase: PHASE4
Conditions: Respiratory Depression, Cannabis Use, Opioid Use
Sponsor: Leiden University Medical Center

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1
 
Influence of ∆9-tetrahydrocannabinol (THC) on oxycodone induced 
ventilatory depression in healthy volunteers 
  
 
 
Protocol ID 
P21.030 
Short title 
COXY study 
EudraCT number  
2021-000083-29 
CCMO number 
NL76443.058.21 
Version 
1.2 
Date 
17-Jun-2021 
Coordinating investigator/project 
leader 
 
Albert Dahan MD PhD Department of Anesthesiology, 
Leiden University Medical Center, Albinusdreef 2, 2333 ZA 
Leiden, Netherlands 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
Dr. Monique van Velzen, Department of Anesthesiology, 
Leiden University Medical Center, Albinusdreef 2, 2333 ZA 
Leiden, Netherlands 
Investigators 
 
Data analysis 
Drs. Jan van Dam 
Drs. Rutger van der Schier 
Dr. Erik Olofsen 
Department of Anesthesiology, Leiden University Medical 
Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Leiden University Medical Center 
Albinusdreef 2, 2333 ZA Leiden, Netherlands 
 
 
Subsidising party 
LUMC 
Independent expert (s) 
Dr. Elise Sarton, Department of Anesthesiology, Leiden 
University Medical Center 
 
Laboratory sites 
Analytical Biochemical Laboratory (ABL) B.V., Assen 
Pharmacy  
Pharmacy of the Leiden University Medical Center 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Research Department: 
 
Prof. Dr. Albert Dahan 
 
 
 
Principal investigator: 
Dr. Monique van Velzen 
 
 
 
 
 

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TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE 
6 
 
2. 
OBJECTIVES 
7 
 
3. 
STUDY DESIGN 
8 
 
4. 
STUDY POPULATION 
11 
 
5. 
TREATMENT OF SUBJECTS 
12 
 
6. 
INVESTIGATIONAL PRODUCT 
13 
 
7. 
NON-INVESTIGATIONAL PRODUCT 
16 
 
8. 
METHODS 
17 
 
9. 
SAFETY REPORTING 
19 
 
10. 
STATISTICAL ANALYSIS 
21 
 
11. 
ETHICAL CONSIDERATIONS 
22 
 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
24 
 
13. 
STRUCTURED RISK ANALYSIS 
26 
 
14. 
REFERENCES 
28 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR General Assessment and Registration form (ABR form), the application form 
that is required for submission to the accredited Ethics Committee; in Dutch: 
Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
AE Adverse Event 
AR Adverse Reaction 
CA Competent Authority 
CCMO Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV Curriculum Vitae 
DSMB Data Safety Monitoring Board 
EU European Union 
EudraCT 
ET 
European drug regulatory affairs Clinical Trials  
End-tidal 
GCP Good Clinical Practice 
GDPR General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
HCVR 
IB 
Hypercapnic ventilatory response  
Investigator’s Brochure 
IC Informed Consent 
IMP Investigational Medicinal Product  
IMPD 
IR 
Investigational Medicinal Product Dossier  
Immediate release 
METC  Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
(S)AE (Serious) Adverse Event  
SPC 
 
SpO2 
Summary of Product Characteristics; in Dutch: officiële productinformatie 
IB1-tekst 
Oxygen saturation 
SUSAR 
THC  
Suspected Unexpected Serious Adverse Reaction 
∆9-tetrahydrocannabinol 
UAVG Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
WMO Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Opioid misuse and abuse are common problems in the Western world. The rate of unintentional 
drug overdose is rapidly increasing, not only in the Unites States but also in the Netherlands. Additionally, it 
is well known that opioids are often used (and abused) in combination with other legal or illicit substances, 
for example cannabis, including medicinal (i.e. doctor prescribed) cannabis. A major opioid-induced adverse 
effect is respiratory depression and there are no data that show how oxycodone interacts with cannabis on 
the ventilatory control system. An appreciable effect is possible given the sedative effects of cannabis. 
Moreover, we previously showed that combining even a low dose of oxycodone (20 mg) with ethanol 
increased the likelihood of an apneic event (van der Schrier et al. Anesthesiology 2017; 102: 115-122). 
Because of this side effect and also due to the rising number of addicted chronic opioid users, there is an 
increasing imminent societal, political and medical interest in advancing research on opioids, opioid-drug 
interaction and alternatives for the treatment of various chronic illnesses and chronic pain.  
 
Hypothesis: We hypothesize that cannabis will amplify the ventilatory depressant effect of oxycodone (primary 
end-point).  
 
Objective: The objective of the study is to quantify the interactive effect of ∆9-tetrahydrocannabinol (THC) and 
oxycodone on ventilatory control.  
 
Study design: Double blind, randomized cross-over, placebo-controlled design. 
 
Study population: Healthy human volunteers between the age of 18 and 45 years old.  
 
Intervention:  
Visit A: placebo capsule at t = 0 min + Bedrocan (22.4 mg THC) at t = 90 and 270 min; 
Visit B: oxycodone 20 mg at t = 0 min + Bedrocan (22.4 mg THC) at t = 90 and 270 min. 
 
Main study parameters/endpoints:  
Primary endpoint: The effect of inhaled THC on ventilation at an end-tidal PCO2 = 55 mmHg without and with 
concomitant intake of 20 mg oxycodone immediate release (IR) capsule in healthy volunteers 120 min after 
oxycodone intake.  
Secondary endpoints: (1) Outcome of Bowdle and Bond & Lader questionnaires; (2) Level of sedation; (3) 
Hemodynamics; (4) Cognition (p-deletion test); (5) Pain Pressure Threshold; (6) slope of the hypercapnic 
ventilatory response; (7) plasma concentrations of THC, 11-OH-THC and oxycodone; a secondary analysis 
will be performed on the pharmacokinetic and pharmacodynamic data (PKPD modeling). 
 
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The 
burden/risks for the volunteers are the occurrence of side effects from cannabis or oxycodone. Oxycodone 
may induce opioid-typical side effects such as respiratory depression (research endpoint), nausea/vomiting 
and sedation, of which nausea and vomiting is most burdensome. Other side effects, which are also 
cannabis related, include drug high, euphoria/dysphoria, dizziness/lightheadedness. During the study, we 
will closely monitor the subjects and treat side effects, most importantly nausea by administration of an 
antiemetic.  

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1. INTRODUCTION AND RATIONALE 
 
Opioids are commonly prescribed for moderate to severe pain. While initially intended for acute and 
cancer pain, opioids are currently frequently considered and prescribed in chronic noncancer pain. A 
consequence of this behavior is the increase in opioid misuse and abuse. The rate of unintentional 
drug overdose is rapidly increasing, not only in the Unites States but also in the Netherlands. A 
potential lethal consequence of opioid overdose is opioid-induced respiratory depression. 
Additionally, it is well known that opioids are often used (and abused) in combination with other 
legal or illicit substances, for example alcohol, benzodiazepines or cannabis, including medicinal (i.e. 
doctor prescribed) cannabis. We previously showed that combining ethanol with oxycodone (20 mg) 
increases respiratory depression, indicative of a dangerous alcohol-opioid combination (van der 
Schrier et al. Anesthesiology 2017; 102: 115-122). There are no data on the interaction between 
oxycodone and cannabis on the ventilatory control system. In our opinion, there is the false premise 
that cannabis has no effect on breathing. Apart from a direct effect on receptors in the brainstem, 
the sedative effects of cannabis may compromise breathing. Because of this side effect and also due 
to the rising number of addicted chronic opioid users, there is an increasing imminent societal, 
political and medical interest in furthering research on opioids, opioid-drug interaction and 
alternatives for the treatment of various chronic illnesses and chronic pain. Additionally, we expect 
that many patients at home using oxycodone, also use (coffeeshop) cannabis.  
 
In this study we will measure the effect of Bedrocan which contains primarily ∆9-
tetrahydrocannabinol (THC) and a minute quantity cannabidiol (CBD), on ventilation at 55 mmHg 
end-tidal PCO2 in 20 healthy volunteers and the combination of THC and 20 mg oral oxycodone 
immediate release capsules. Primary endpoint is the effect of inhaled THC on ventilation at end-tidal 
PCO2 = 55 mmHg without and with concomitant intake of 20 mg oxycodone immediate release (IR) 
capsule in healthy volunteers 120 min after oxycodone intake. In this study we will use the Volcano 
cannabis vaporizer to vaporize 100 mg Bedrocan into a 6 L balloon. Volunteers will inhale the 
cannabis vapor from the balloon.  
 
 
 

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2. OBJECTIVES 
 
Primary objective: To measure the effect of inhaled THC (100 mg Bedrocan) on ventilation at 
isohypercapnia (end-tidal PCO2 = 55 mmHg) without and with concomitant intake of 20 mg 
oxycodone immediate release (IR) capsule in healthy volunteers 90 min after oxycodone intake.  
 
Secondary objective: To measure the effect of inhaled THC (100 mg Bedrocan) without and with 
concomitant intake of 20 mg oxycodone immediate release (IR) on  
- occurrence of apneic events; 
- occurrence of desaturation events; 
- slope of the hypercapnic ventilatory response; 
- baseline ventilation; 
- psychomimetic side effects as measured by Bowdle and Bond & Lader questionnaires; 
- cognition (p-deletion test) 
- pain pressure threshold 
- plasma concentrations of THC and oxycodone; 
- blood pressure and heart rate. 
 

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3. STUDY DESIGN 
 
3.1 General study design 
The design of the study is randomized, placebo-controlled crossover. Each subject will be studied 
twice, on one occasion he or she will receive THC and a placebo opioid capsule, and on the other 
occasion THC and an oxycodone capsule. The visits to the lab will be randomized, the washout period 
between the two occasions is at least 10 days. Subjects will be evaluated by a physician at screening 
and only healthy volunteers, aged 18-45 years, with a body mass index < 30 kg.m-2, are eligible to 
participate in the study.  
 
Upon arrival in the laboratory (K5-120), we will perform a urinary drug test and breath alcohol test. 
When these tests are positive, the subject is excluded from further participation. A venous and an 
arterial line will be placed. The venous line is used for fluid administration (NaCl/Glucose 50-100 
ml/h), the arterial line is for blood sample drawing.  
 
Next, the first hypercapnic ventilatory responses (HCVR) will be obtained (t = -30 min). This is the pre-
drug baseline measurement. At t = 0, the subjects will receive 20 mg oxycodone immediate release 
or placebo. Next, we will obtain HCVRs at 1-hour intervals until 6 hours after oxycodone/placebo 
intake. At t = 1.5 h and at t = 4.5 h the subject will inhale 100 mg Bedrocan. Breathing will be 
measured using the “dynamic end-tidal forcing” (DEF) system. At specific time points we will draw 10 
mL blood for measurement of drug concentrations. After 8 hours of measurement, we will assess 
whether the HCVR is still depressed. If so, we will take another measurement at t = 9 h and reassess 
the HCVR. If still depressed, a last response will be obtained at t = 10 h. If necessary, the subject will 
stay overnight in the hospital. This will be decided by the physician-investigator. For example, the 
subject may still be sedated.  
 
3.2 The hypercapnic ventilatory response 
To obtain the HCVR curve, the subject will rebreathe a gas mixture from a 6 L rebreathing balloon 
bag containing 7% carbon dioxide in 93% oxygen. The slope of the response and ventilation at 55 
mmHg will be used in the analysis.  
 
3.3 Drug intake 
3.3.1 Oxycodone intake: At t = 0, the subject will ingest 1 oxycodone 20 mg immediate release or a 
placebo capsule with 100 mL water. Both drugs will be obtained from the LUMC pharmacy.  
 
3.3.2 Cannabis inhalation: Bedrocan is vaporized using the CE-marked Volcano Medic vaporizer 
(Storz & Bickel GmbH & Co, Tuttlingen, Germany), a safe and reliable method of intrapulmonary 
administration of cannabinoids. The Volcano heats the homogenized plant material to 210 °C to 
allow for conversion of the THC acid and CBD acid into THC and CBD vapor for inhalation. The 
complete 100 mg from the glass vial will be entered into the vaporizing chamber of the Volcano 
Medic. The vapor will be collected in a 6-L plastic balloon that, after inflation, is detached from the 
vaporizer and subsequently equipped with a mouthpiece for inhalation. It is our experience that the 
full content of the balloon is inhaled without any problems within 3-5 min.  
 
The Bedrocan cannabis variety contains 22% THC (220 mg per gram) and less than 1%CBD. It is 

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developed in the Netherlands out of a requirement by the Dutch Health Ministry to have a “high 
THC” variety available to patients. We will administer 100 mg Bedrocan that contains 22.4-mg THC 
and less than 1-mg CBD, twice. Bedrocan will be obtained via the Bureau voor Medicinale Cannabis 
(BMO), a governmental organization (VWS) that obtains cannabis from Bedrocan Int. BV in 
Veenendaal, The Netherlands.  
 
3.4 Blood sampling 
Ten mL blood samples will be obtained on 14 occasions on each visit (total volume = 112 mL per visit) 
at t = 30 and 60 min after oxycodone intake and at t = 5, 20, 40, 60, 120, 180, 185, 200, 220, 240, 300 
and 360 min after the first THC inhalation. From these sample, the following drugs will be measured: 
oxycodone, THC, THC’s metabolite 11-OH-THC and cannabidiol (CBD). CBD is measured as it is 
expected that some minor quantities of CBD are present in Bedrocan.  
 
Arterial blood will be collected in EDTA tubes. After blood collection the tubes will preferably be put 
in ice water in aluminum foiled containers, will be centrifuged within one hour for 10 minutes at 
2000 G at 4 °C. The handling of samples will be done with the lights switched off. The plasma will be 
equally divided in 2 tubes (Brown Sarstedt) (primary and back-up sample). Plasma samples will be 
stored at a temperature of -80 °C and blood samples will be sent to Analytical Biochemical 
Laboratory (ABL) B.V., Assen, The Netherlands on dry-ice. Pharmacokinetic analysis will be performed 
using a validated assay. Determination of drug concentrations will be performed using liquid 
chromatography with tandem-mass spectrometer detection (LC-MS/MS). Analysis of the samples and 
acceptance criteria are indicated in ABL Standard Operating Procedure (SOP) 0251. 
 
3.5 Questionnaires 
Psychedelic effects are measured using visual analog scales ranging from 0 (no effect) to 10 cm 
(maximum effect) of the Bowdle and Bond & Lader questionnaires. 
 
BOWDLE QUESTIONNAIRE: Three factors of psychedelic effects can be derived from the Bowdle 
questionnaire: drug high, internal perception, and external perception. Internal perception reflects 
inner feelings that do not correspond with the reality and is derived from questions regarding the 
hearing of unrealistic voices or sounds and having unrealistic thoughts and paranoid or anxious 
feelings. The external perception indicates a misperception of an external stimulus or change in the 
awareness of the subject’s surroundings and is derived from questions regarding the change of body 
parts, the change of surroundings, the altered passing of time, the difficulty of controlling thoughts, 
and the change in color and sound intensity.  
 
BOND & LADER: The Bond and Lader scales are calculated from sixteen 100 mm visual analog scales. 
The endpoints are set at antonymous word pairs such as ‘alert–drowsy’, ‘well coordinated–clumsy’, 
‘mentally slow–quick witted’ and ‘incompetent–proficient’. The study participant's task is to make a 
mark on each scale at the point that best describes how they currently feel considering that the two 
anchors reflect the greatest extent they experience each state. Responses from these 16 scales are 
then scored to yield three main factors of alertness (alert, strong, clear-headed, coordinated, 
energetic, quick-witted, attentive, proficient, interested), contentment (contented, happy, amicable, 
gregarious, tranquil), and calmness (calm, relaxed). A high score indicates impairment. 
 

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3.6 Pain pressure resting 
We will use the FPN 100 N Algometer (FDN 100, Wagner Instruments Inc., Greenwich, CT, USA; Rolke 
et al., 2005) to deliver pressure pain on a skin area of 1 cm2 between thumb and index finger. The 
FDN 100 has a force capacity (± accuracy) of 100 ± 2 N (10 ± 0.2 kgf) and graduation of 1 N (100 gf), 
respectively. A gradually increasing pressure is manually applied and the subjects are asked to 
indicate when the procedure becomes painful (pressure pain threshold, PPTh). 
 
 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Healthy volunteers of either sex with earlier experience with cannabis (>2 lifetime exposures and 
<2x/week in the last 12 months). 
 
4.2 Inclusion criteria 
- aged 18-45 years,  
- body mass index < 30 kg.m-2,  
- able to understand the written informed consent form,  
- able to communicate with the staff,  
- able and willing to complete the study procedures, 
- signed the informed consent form, 
- deemed suitable by the investigators. 
 
4.3 Exclusion criteria 
- Presence or history of any medical or psychiatric disease (incl. a history of substance abuse, anxiety, 
or the presence of a painful syndrome such as fibromyalgia); 
- Use of any medication in the three months prior to the study (incl. paracetamol or other pain 
killers), except for oral contraceptives (females); 
- Use of more than 21 alcohol units per week; 
- Use of cannabis in the 4 weeks prior to the study; 
- A positive urinary drug test or a breath alcohol test at screening or on the morning of the 
experiment; 
- Pregnancy, lactating or a positive pregnancy test on the morning of the experiment; 
- Participation in another drug trial in the 60 days prior to dosing. 
 
4.4 Sample size calculation 
There are no prior data on the interactive effect of cannabis and oxycodone on isohypercapnic 
breathing. If we extrapolate results of the ethanol data (van der Schrier et al., 2017) to the current 
study, we estimate an effect size of 5 L/min of adding THC to oxycodone with SD 6 L/min. We 
calculated a sample size of 18 subjects with alpha = 0.05 and 1 – beta = 0.90. To take any 
uncertainties into account we increased the group size to 20. 
 
 
 
 
 
 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
- Oxycodone (oxycontin) or placebo will be ingested on t = 0 min. The dose is 20 mg, the formulation 
an immediate release capsule.   
 
- BedrocanTM will be inhaled at 90 min and again at 270 min. The dose is 100 mg containing about 
22% THC.  
-Placebo capsules will be obtained from the LUMC pharmacy.  
 
5.2 Use of co-intervention  
Not applicable. 
 
5.3 Escape medication 
In principle no escape medication is needed. However, in case of nausea or vomiting, ondansetron 4 
mg iv may be administered (max. dose 12 mg). Additionally, in case of severe respiratory depression 
(as judged by the investigator), naloxone 400 mug may be given intravenously (possibly repetitive, 
no. max. dose). 
 
 
 

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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational product 
 
- Oxycodone (oxycontin) is an opioid analgesic and registered in the Netherlands for the treatment 
of pain. The SpC is submitted with the protocol. An oxycodone immediate release capsule will be 
administered orally in a dose of 20 mg. We have done previous studies with oxycodone and know 
that its respiratory effects are moderate with plasma concentrations not exceeding 50 ng/mL. In the 
graph below, first results from P18.212 are given, showing the mean ± SD concentration of 
oxycodone immediate 20 are shown. An important observation is that after 24 h no oxycodone is 
present in the body and that after 5 hours the concentration dropped to levels < 15 ng/mL.  
 
- BedrocanTM variety is a strain of cannabis characterized by circa 22% THC (220 mg per gram) and 
less than 1% CBD. Bedrocan® was developed in the Netherlands out of a requirement by the Dutch 
Health Ministry to have a “high THC” variety available to patients. It is a plant type bred because of 
its high yield, optimal growth characteristics, and derived from the popularly known “Jack Herer” 
cannabis variety. 100 mg of this study drug contains approx. 22 mg of THC for inhalation.  
 
 
 
Figure 1. Oxycodone concentration following intake of 20 mg immediate release oral capsule at t = 0 min. Data are mean ± 
SD of 6 subjects and are from protocol P18.212.  
 
Bedrocan is vaporized using the CE-marked Volcano Medic vaporizer (Storz & Bickel GmbH & Co, 
Tuttlingen, Germany), a safe and reliable method of intrapulmonary administration of cannabinoids. 
The Volcano heats the homogenized plant material to 210 °C to allow for conversion of the THC acid 
and CBD acid into THC and CBD vapor for inhalation. The vapor will be collected in an 8-L plastic 
balloon that, after inflation, is detached from the vaporizer and subsequently equipped with a 
mouthpiece for inhalation. It is our experience that the full content of the balloon is inhaled without 
any problems within 3-5 min.  
 
We performed an earlier study with Bedrocan in 20 chronic pain patients, see Figure 2 (P15.316).THC 
concentrations (green symbols) reach about 100 ng/mL just after inhalation followed by an 

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exponential decay towards concentrations < 1 ng/mL after 3 hours. This indicates that at the end of 
the experiments no active levels of cannabis remain in plasma.  
-  Placebo capsules will be obtained from the LUMC pharmacy.  
 
6.2 Summary of findings from non-clinical studies 
Oxycodone, see submitted SPC. 
Bedrocan, see submitted Investigators Brochure and IMPD. 
Placebo, see submitted SPC. 
 
 
Figure 2. THC (green), 11-OH-THC (blue) and CBD (orange) concentrations following inhalation of 100 mg Bedrocan. Data 
from P15.316 obtained in 20 chronic pain patients. Data are mean ± 95% confidence interval. 
 
6.3 Summary of findings from clinical studies 
- Oxycodone, see submitted SPC and publications from van der Schrier et al. (Anesthesiology 2017 
and Br J Anaesth, 2019). These publications describe the safety of 20 mg oral oxycodone treatment in 
healthy volunteers in a similar population of subjects as being tested in the current study. 
- Bedrocan, see submitted Investigators Brochure and IMPD and publication from van den Donk et al. 
(Pain, 2019). This publication shows the safety of 100 mg Bedrocan in a more vulnerable population 
than studied by us.  
- Placebo, see submitted SPC. 
 
6.4 Summary of known and potential risks and benefits 
This interventional proof-of-concept study has no intended benefit in terms of disease load 
reduction. The study in healthy volunteers attempts to understand the interaction between 
oxycodone and cannabis on ventilatory control. The gained information is of extreme importance 
given the current opioid epidemic and high number of opioid toxicities in the world, including the 
Netherlands.   

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Opioids produce several side effects. These side effects are the topic of the current study. Since the 
study is performed under highly controlled and monitored conditions, the occurrence of temporary 
side effects will have limited impact on the subject. We expect and will measure respiratory 
depression. In case of severe respiratory depression, we can administer naloxone. In the last 25 years 
that we have performed these studies, we never needed to administer naloxone because of 
respiratory depression. Additional side effects include nausea and vomiting (to be treated with an 
antiemetic) and sedation.  
Cannabis does produce side effects, most importantly nausea/vomiting (to be treated with an 
antiemetic), sedation and psychomimetic side effects of which drug high is most important. These 
side effects decline rapidly within 2-3 hours after inhalation (See van de Donk et al., Pain 2019).  
 
6.5 Description and justification of route of administration and dosage 
Oxycodone (and placebo) will be administered orally. This is a routine form of administration. 
Bedrocan will be inhaled, a form of administration that is highly effective with an uptake > 66% of 
vapor.   
 
6.6 Dosages, dosage modifications and method of administration 
See 6.1 
6.7 Preparation and labelling of Investigational Medicinal Product 
The IMPs will be obtained from the LUMC pharmacy. They are responsible for labelling and 
packaging.  
 
6.8 Drug accountability 
All study products are obtained from the pharmacy. Remaining products will be destroyed by the 
researchers, and noted on the Case Record Form.  
 
 
 
 

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7. NON-INVESTIGATIONAL PRODUCT 
7.1 Name and description of non-investigational product(s) 
7.1.1 The Volcano Vaporizer 
The Volcano Vaporizer is a CE-marked device. It is produced by Storz & Bickel GmbH & Co. 
(Tuttlingen, Germany).  
7.1.2 Ventilation measurement 
Ventilation will be measured with the CE-marked ExSpiron device; see cosubmitted files. 
 
Name of 
device 
Manufacturer 
Model 
CE conform 
93/42/EEG of 
EU/2017/745 
(Medical devices) 
 
Conform 
intended use as 
described in the 
instruction 
manual?  
Volcano 
Vaporizer  
Storz & Bickel 
GmbH & Co 
Mighty Medic 2 
 
Inventory number: 
will follow 
Yes 
Yes 
ExSpiron™ 
Minute 
Ventilation 
Monitor 
Innomed Benelux 
1Xi 
 
Inventory number: 
20-800-1045 
Yes 
Yes 
 
7.2 Summary of findings from non-clinical studies 
NA 
7.3 Summary of findings from clinical studies 
NA 
7.4 Summary of known and potential risks and benefits 
NA 
7.5 Description and justification of route of administration 
NA 
7.6 Dosage, dosage modification and method of administration 
NA 
7.7 Preparation and labelling of Investigational Medicinal Product 
NA 
 
7.8 Drug accountability 
NA 
 
 

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8. METHODS  
8.1 Study parameters/endpoints 
 
8.1.1 Main study parameter/endpoint 
Primary endpoint is the effect of inhaled THC on ventilation at end-tidal PCO2 = 55 
mmHg without and with concomitant intake of 20 mg oxycodone immediate release (IR) 
capsule in healthy volunteers 120 min after oxycodone intake.  
 
8.1.2 Secondary study parameters/endpoints (if applicable) 
 
 
- occurrence of apneic events; 
 
 
- occurrence of desaturation events; 
 
 
- slope of the hypercapnic ventilatory response; 
 
 
- baseline ventilation; 
- psychomimetic side effects as measured by Bowdle and Bond & Lader 
questionnaires; plasma concentrations of THC and oxycodone; 
 
 
- blood pressure and heart rate. 
 
8.1.3 Other study parameters (if applicable) 
 
 
NA 
 
8.2 Randomization, blinding and treatment allocation 
The sequence of visit will be randomized using a randomization list generated within CASTOR EDC 
prior to dosing.  
 
8.3 Study procedures 
The estimated time line of the study is as follows: 
 
8:30 arrival in the laboratory at K5-120; urine drug and alcohol breath testing; 
8:45 placement of intravenous and arterial line. 
9:00 baseline pain pressure test, baseline questionnaires, baseline blood sample 
9:30 baseline Hypercapnic ventilatory response (HCVR); 
10:00 intake of placebo/oxycodone 
11:00 HCVR #2 
11:30 inhalation of 100 mg Bedrocan 
12:00 HCVR #3 
13:00 HCVR #4 
14:00 HCVR #5 
14:30 inhalation of 100 mg Bedrocan 
15:00 HCVR #6 
16:00 HCVR #7 
17:00 HCVR #8 
 
Assessment of the subject at 17:30. If HCVR is still depressed two additional HCVR may be obtained 
at 18:00 and 19:00 hours. 
Subject returns home or stays overnight (decided upon the discretion of the attending physician-
investigator). Our experience is that most if not all subjects will be sufficiently fit to go home. 
 

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18 
 
Blood samples will be drawn according to the following scheme: 
10:30; 11:00, 11:35; 11:50; 12:10; 12:30; 13:30; 14:30; 14:35; 14:50; 15:10; 15:30; 16:30; 17:30.  
 
Bowdle and Bond & Lader Questionnaires are taken at 10:30; 11:30; 12:30; 13:30; 14:30; 15:30; 
16:30; 17:30. All questionnaires are taken 5 min prior to blood sampling.  
 
Pain pressure threshold will be measured at 10:25, 10:55, 11:30; 11:45; 12:05; 12:25; 13:25; 14:25; 
14:30; 14:45; 15:05; 15:25; 16:25; 17:25.  
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for any reasons. 
 
 
8.4.1 Specific criteria for withdrawal (if applicable) 
 The most important criterium for withdrawal is that the subject indicates that he or she 
want to terminate the experiment. Additionally, we will terminate the experiment in case of 
a life-threatening adverse event (to be judged by the physician-investigator) or any other 
condition that may affect the health of wellbeing of the subject.  
 
Rules for administration of naloxone in case of a respiratory event are:  
 
- loss of respiratory activity for 3 min or longer, despite active stimulation of the subject; 
 
- and increase in end-tidal PCO2 to 9 kPa or greater for more than 3 min; 
 
- SpO2 < 85% for more than 3 min despite administration of supplemental oxygen. 
In all three cases, when respiration is resumed, respiratory measurements will continue for as 
long as needed to ensure complete return of respiration to control levels. However, if this  occurs 
prior to the second Bedrocan inhalation, the second inhalation will not be performed. Given the 
ample experience that the researchers have with performing studies on opioid effect on 
breathing, we expect that the probability of such events are extremely small. 
 
8.5 Replacement of individual subjects after withdrawal 
Subjects will be replaced in case of withdrawal.  
 
8.6 Follow-up of subjects withdrawn from treatment 
As indicated above, in case stopping rules were met and naloxone was administered, respiratory 
measurements will continue for as long as possible to ensure complete return of respiration to 
control levels. It may additionally be decided to keep the subject overnight. Only when respiration 
has returned to baseline levels, the subject will be sent home (under supervision).  
 
8.7 Premature termination of the study 
When a serious adverse event occurs related to treatment, the ethics committee will be notified and 
further experiments will be put on hold until the ethics committee has re-evaluated the experiments 
in close cooperation with the researchers. We do not plan to institute a Data Safety Committee for 
the reason that the researchers are all experts on the topic of opioid-induced respiratory depression 
and the probability of such events are extremely small. Overall, given our experience and expertise, 
we judge that this experiment to have a negligible to moderate risk.  
 

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19 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO (Medical Research Involving Human Subjects 
Act), the sponsor will suspend the study if there is sufficient ground that continuation of the study 
will jeopardize subject health or safety.  The sponsor will notify the accredited METC (Human Ethics 
Committee) 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 the investigational product,  trial procedure/ the experimental 
intervention. All adverse events reported spontaneously by the subject or observed by the investiga-
tor or their staff will be recorded. 
 
9.2.2. Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- results in death; 
- is life threatening (at the time of the event); 
- requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- results in persistent or significant disability or incapacity; 
- is a congenital anomaly or birth defect; 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. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor (LUMC) without undue delay after obtaining 
knowledge of the events, except for the following SAEs: any SAE not related to study medication or 
study procedures.  
 
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 period of maximum 15 days after the sponsor has first 
knowledge of the serious adverse events. SAEs that do not require reporting will be reported in the 
annual safety report.  
 
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. 
 

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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: 
- Summary of Product Characteristics (SPC) for an authorized medicinal product; 
- Investigator’s Brochure for an unauthorized medicinal product. 
 
The sponsor will report expedited the following SUSARs 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 be maximal 7 days for a preliminary report with another 8 days for 
completion of the report. 
 
9.3 Annual safety report 
The annual safety report will be combined with the annual progress 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 until the 
end of study, as defined in the protocol. 

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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter 
The primary end-point is ventilation at isohypercapnia (VE55). To obtain VE55 we will estimate the 
slope of the HCVR R (The R Foundation for Statistical Computing, www.r-project.org, accessed 
January 1, 2017) and next calculate ventilation at an end-tidal carbon dioxide concentration of 55 
mmHg.  
 
We with compare VE55 between the two treatment arms by considering baseline values (prior to any 
drug use) and VE55 at t = 120 min after oxycodone or placebo intake with visit, and oxycodone 
treatment as fixed factors and subject as a repeated statement and baseline value as covariate.  
P < 0.05 is considered significant.  
 
Additionally, we will perform a pharmacokinetic-pharmacodynamic data analysis in NONMEM. The 
model to be used in the NONMEM analysis has not been specified as yet but will be of the form:  
 
Figure 6. Schematic diagram of a possible NONMEM pharmacokinetic-pharmacodynamic model of the interactive effects of 
oxycodone and THC on ventilation. Vo is baseline value, V1 and V2 the volumes of the pharmacokinetic compartments 1 
and 2, with corresponding clearances CL. Ke0 is the blood-effect-site equilibration rate constant.  
 
10.2 Secondary study parameter(s)  
All secondary parameters will be presented as mean ± SD or 95% confidence interval, median 
(interquartile range). Data will be analyzed using an explorative approach.  
 
10.3 Other study parameters 
NA.  
10.4 Interim analysis (if applicable) 
NA. 
 

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11. ETHICAL CONSIDERATIONS 
 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (version 
amended in Fortaleza, Brasil, 2013) and in accordance with the Medical Research Involving Human 
Subjects Act (WMO). The PI and junior researcher are BROK certified. No additional harm or benefit 
is expected upon participation within this study. 
 
11.2 Recruitment and consent 
Eligible subjects will be approached before inclusion by telephone for brief oral information by one 
of the researchers. If the subject is willing to participate, written information will be provided and 
informed consent will be obtained prior to further screening. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
NA. 
 
11.4 Benefits and risks assessment, group relatedness 
This interventional proof-of-concept study has no intended benefit in terms of disease load 
reduction. The study in healthy volunteers attempts to understand the interaction between 
oxycodone and cannabis on ventilatory control. The gained information is of importance given the 
current opioid epidemic and high number of opioid toxicities in the world, including the Netherlands. 
We contend that the results of this study may be extrapolated to the general population.    
Opioids produce several side effects. These side effects are the topic of the current study. Since the 
study is performed under highly controlled and monitored conditions, the occurrence of temporary 
side effects will have limited impact on the subject. We expect and will measure respiratory 
depression. In case of severe respiratory depression, we can administer naloxone. In the last 25 years 
that we perform these studies, we never needed to administer naloxone because of respiratory 
depression. Additional side effects include nausea and vomiting (to be treated with an antiemetic) 
and sedation.  
Cannabis does produce side effects, most importantly nausea/vomiting (to be treated with an 
antiemetic), sedation and psychomimetic side effects of which drug high is most important. These 
side effects decline rapidly within 2-3 hours after inhalation (See van de Donk et al., Pain 2019).  
10.5 Compensation for injury 
The risk of injury as a result of this study is considered small. However, the LUMC has insured this risk 
by a liability insurance, in accordance with article 7, subsection 6 of the WMO. 
 
The sponsor (also) has an insurance policy in accordance, with the legal requirements in the 
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical Research 
in Humans of 23th June 2003). This insurance provides cover for damage to research patients 
through injury or death caused by the study: 
1. € 650.000,-- (i.e. six hundred and fifty thousand Euro) for death or injury for each subject who 
participates in the Research; 

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2. € 5.000.000,-- (i.e. five million five hundred thousand Euro) for death or injury for all subjects who 
participate in the Research; 
3. € 7.500.000,-- (i.e. seven and a half million Euro) for the total damage incurred by the organisation 
for all damage disclosed by scientific research by the sponsor in each year of insurance coverage. 
 
10.6 Incentives (if applicable) 
Volunteers will be reimbursed for their participation in the study. They will receive euro 400  for 
completion of all 2 sessions (or 20 euros/h) or 10 euros per hour participated in the study when the 
experiment is prematurely terminated for any reason. per session. 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
12.1 Handling and storage of data and documents 
All data from the subjects will be stored under code. Subject-related identifying data will be omitted 
from all secondary documents. The code will be stored digitally on a secured partition of the i:-disk at 
LUMC that is accessible by just the investigators. Other involved parties (monitor, Inspectie, 
Gezondheidszorg en Jeugd) may be granted access to subject data, also subject identifying data, to 
review the research. These involved parties will handle the patient identifying data in a confidential 
manner. The sponsor, local researchers and project leader are responsible for data processing. When 
a subject withdraws consent, data collected until that moment will be used. All data will be stored for 
the length of the study and for 25 years afterwards, for further publication. Blood will be stored until 
analysis and will be destroyed afterwards. All handling of personal data will comply with the Dutch 
Personal Data Protection Act. The Functionaris Gegevensbescherming from the LUMC has been 
informed about the data handling in the study. When subjects have questions or complaints about 
data handling they can contact the Functionaris  Gegevensbescherming (contact information is 
mentioned in the patient information letter). Only data needed to assess study objectives will be 
collected. 
 
12.2 Monitoring and Quality Assurance  
Monitoring will be executed by (internal) monitors of the LUMC according to the monitor plan.  
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 by the completion of data analysis. 
 
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 

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25 
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 
The study will be registered at trialregister.nl prior to recruitment of subjects. The results of the trial 
will be published in a peer-review scientific journal and will be presented on (inter)national scientific 
conferences and meetings. This will be in accordance to the CCMO statement on publication policy. 
 

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13. STRUCTURED RISK ANALYSIS 
 
13.1 Potential issues of concern 
Most important risks related to oxycodone include: sedation, nausea and vomiting, respiratory 
depression. However, we consider none of these a potential issue of concern, since (1) we will 
monitor all subjects continuously during the study, (2) we have ample knowledge on 
pharmacokinetics and pharmacodynamics of oxycodone and consequently on the occurrence, risk 
and treatment of these effects, (3) since all adverse effects are related to drug plasma concentration, 
these events dissipate over time (see for the PK profile Figure 1). Additionally, we have ample 
knowledge on the mechanism of action of oxycodone and are able to terminate all of these effects by 
administration of naloxone. This will immediately resolve respiratory depression and sedation. 
Nausea/vomiting may be treated with antiemetics.  
 
Most important risk of THC include: sedation, nausea and vomiting, and psychomimetic side effects, 
most importantly drug high. However, we consider none of these a potential issue of concern, since 
(1) we will monitor all subjects continuously during the study, (2) we have ample knowledge on 
pharmacokinetics and pharmacodynamics of THC and consequently on the occurrence, risk and 
treatment of these side effects, (3) since all adverse are related to plasma concentration, these 
events dissipate over within 3 hours following inhalation (see for the PK profile Figure 2). 
Additionally, we have ample knowledge on the mechanism of action of THC. Nausea/vomiting may 
be treated with antiemetics.  
 
Most important risks of the combination of THC and oxycodone include: sedation, nausea and 
vomiting, respiratory depression and psychomimetic side effects, most importantly drug high. 
However, we consider none of these a potential issue of concern, since (1) we will monitor all 
subjects continuously during the study, (2) we have ample knowledge on the occurrence, risk and 
treatment of these effects in separate administrations, (3) all adverse events dissipate over time. The 
combination of oxycodone and THC may cause additive effects on sedation, respiratory depression or 
nausea/vomiting. We are able to terminate the opioid part in case of severe side effect by 
administration of naloxone; additionally, we can treat nausea/vomiting with antiemetics. 
 
13.2 Synthesis  
First, the population in which we will perform these experiments (healthy, young volunteers) is not 
considered frail or at risk, and it is our experience that these subjects will be able to complete both 
experimental sessions without consequences. 
 
Second, we will continuously monitor the subjects following administration of oxycodone and/or 
THC. In case the physician-investigator has doubts whether the subject can return home, we will 
continue monitoring during an overnight stay. 
 
Third, in case of serious effects on respiration, the opioid effect may be reversed by administration of 
naloxone.  
 
Fourth, the researchers have ample experience with the administration of even higher doses of 
opioids and THC in volunteers.  

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27 
 
Fifth, the occurrence of side effects is the topic of the current study. Hence all effects of treatment 
on respiration will be logged and is available for analysis.  
 
 
 

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14. REFERENCES 
 
Bedene A, Lijfering WM, Niesters M, van Velzen M, Rosendaal FR, Bouvy ML, Dahan A, van Dorp ELA. Opioid 
prescription patterns and risk factors associated with opioid use in the Netherlands. JAMA Network Open 2019; 
2(8):e1910223. 
 
Dahan A, Kramers K, Schellekens A, Niesters M. Pijnbestrijding: geef opiaten slechts een bijrol. Medisch Contact 
2018. 
 
van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, van Velzen M. An experimental 
randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain 
patients with fibromyalgia. Pain 2019; 160: 860-869. 
 
van der Schrier R, Jonkman K, van Velzen M, Olofsen E, Drewes AM, Dahan A, Niesters M. An experimental 
study on the comparison of the respiratory effects of tapentadol and oxycodone in healthy volunteers. Br J 
Anaesth 2017; 119: 1169-1177 
 
van der Schrier R, Roozekrans M, Olofsen E, Aarts L, van Velzen M, de Jong M, Dahan A, Niesters M. Influence 
of ethanol on oxycodone-induced respiratory depression: a dose-escalating study in young and elderly 
volunteers. Anesthesiology 2017, 126: 534-542. 
 
Vrijmoeth T, Kramers C, Dahan A, Koelemay MJW.  Vermijden van langdurig opiaatgebruik na operatie. NTvG 
2018; 162: D2801.