Open-label, Prospective Study to Assess the Safety, Tolerability, Analgesic Effect and Feasibility of Intranasal Sufentanil/Ketamine in Pediatric Patients With Moderate or Severe Pain, in an Acute Care Setting
Phase: PHASE2
Conditions: Pain
Sponsor: Cessatech A/S

 
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CLINICAL STUDY PROTOCOL 
 
Open-label, prospective study to assess the safety, tolerability, 
analgesic effect and feasibility of IN SUF/KET in pediatric patients 
with moderate or severe pain, in an acute care setting  
Protocol no.: PDC 01-0202 Version 3.2, Date: 18-Sep-2024 Local version CTIS 
EU CT no.: 2023-504023-63-00 
IRAS no: 1006944 
 
 
Investigational medicinal product: Sufentanil(citrate)/ketamine(hydrochloride) for intranasal use 
 
Investigational medicinal product code: CT001 
 
Development phase: 2 
 
Coordinating Investigator:  
 
Birmingham Children's Hospital 
Steelhouse Lane 
Birmingham B4 6NH 
England 
 
Sponsor: 
Cessatech A/S 
Strandvejen 60 
2900 Hellerup Denmark 
 
Contract Research Organization Europe:  
SMERUD Medical Research International AS 
Thunes Vei 2 
N-0274 Oslo 
Norway 
 
  
 
 
CONFIDENTIALITY STATEMENT 
This material is confidential and the property of Sponsor. Its contents must not be disclosed or used 
except as authorised in writing by Sponsor. 
 
 
 
 
 
 

 
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Contact Information 
 
Sponsor 
 
 
Primary contact:  
 
Cessatech A/S 
Strandvejen 60 
2900 Hellerup  
Denmark  
  
 
 
 
Medical monitor:  
 
Cessatech A/S 
Strandvejen 60 
2900 Hellerup  
Denmark  
 
 
 
CRO 
SMERUD Medical Research International AS 
Thunes Vei 2 
N-0274 Oslo 
Norway 
Tel.: +47 23 27 20 00 
Fax: +47 23 27 20 01 
Web: www.smerud.com 
 
 
 
 
SAE reporting 
E-mail: pharmacovigilance@smerud.com 

 
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TABLE OF CONTENTS 
 
CONTACT INFORMATION ..............................................................................................................2 
TABLE OF CONTENTS ...................................................................................................................3 
PROTOCOL OUTLINE.....................................................................................................................6 
LIST OF ABBREVIATIONS .......................................................................................................... 10 
1 
INTRODUCTION ................................................................................................................... 11 
1.1 
BACKGROUND .................................................................................................................. 11 
1.2 
RATIONALE FOR DEVELOPMENT OF CT001 NASAL SPRAY ................................................... 11 
1.3 
DRUG CLASS ................................................................................................................... 11 
1.4 
PREVIOUS NON-CLINICAL AND CLINICAL STUDIES .............................................................. 12 
 
Non-Clinical Studies .............................................................................................. 12 
 
Clinical studies ....................................................................................................... 12 
1.5 
ONGOING CLINICAL STUDY WITH CT001 ........................................................................... 13 
1.6 
RATIONALE OF THE PRESENT STUDY................................................................................. 14 
1.7 
ETHICAL CONSIDERATIONS ............................................................................................... 14 
 
Risk and inconveniences to the patients ............................................................... 14 
 
Euphoria and psychological dependency .............................................................. 15 
1.8 
BENEFIT-RISK ASSESSMENT ............................................................................................. 15 
 
Pregnancy and acute opioid and ketamine use..................................................... 16 
2 
OBJECTIVES ........................................................................................................................ 17 
3 
POPULATION ....................................................................................................................... 17 
3.1 
INCLUSION CRITERIA ........................................................................................................ 17 
3.2 
EXCLUSION CRITERIA ....................................................................................................... 18 
3.3 
RECRUITMENT AND SCREENING ........................................................................................ 18 
 
Pregnancy and contraceptive guidance ................................................................ 19 
3.4 
LIFESTYLE CONSIDERATIONS ............................................................................................ 19 
 
Meals and dietary restrictions ................................................................................ 19 
 
Activity restrictions ................................................................................................. 19 
 
Driving and bicycling .............................................................................................. 19 
4 
STUDY PROCEDURES ........................................................................................................ 20 
4.1 
OVERALL STUDY DESIGN.................................................................................................. 20 
4.2 
CLINIC VISITS ................................................................................................................... 21 
4.3 
ASSESSMENTS ................................................................................................................. 25 
 
Medical and surgical history .................................................................................. 25 
 
Pain intensity assessments ................................................................................... 25 
 
Assessment of sedation ......................................................................................... 26 
 
Vital signs............................................................................................................... 26 
 
Assessment of the nasal tolerability ...................................................................... 26 
 
Assessment of medication errors .......................................................................... 27 
 
Need for additional analgesics .............................................................................. 27 
 
Demographics and weight ..................................................................................... 27 
 
Adverse events ...................................................................................................... 27 
 
Concomitant medication ........................................................................................ 27 
 
Any medication given for AEs during the time from enrolment to follow up should be 
entered in the eCRF. Any ‘rescue medication’ (described as additional analgesics due to 
insufficient effect of IMP during the 60 min after the last dose of IMP), should be entered in 
the eCRF. The time given should also be noted.Feasibility / Treatment satisfaction............ 27 

 
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Text/telephonic follow-up for safety ....................................................................... 28 
4.4 
PARTICIPANT WITHDRAWAL .............................................................................................. 28 
4.5 
REPLACEMENT OF PARTICIPANTS ...................................................................................... 29 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................................... 29 
 
CT001 .................................................................................................................... 29 
 
Non-investigational medicinal products (NIMPs) ................................................... 30 
5.2 
SUPPLY, PACKAGING, LABELLING, HANDLING AND STORAGE .............................................. 30 
5.3 
DOSAGE AND ADMINISTRATION ......................................................................................... 30 
5.4 
NUMBER OF PARTICIPANTS TREATED IN DIFFERENT AGE GROUPS ..................................... 31 
5.5 
IMP ACCOUNTABILITY ...................................................................................................... 31 
6 
RESPONSE VARIABLES AND ENDPOINTS ...................................................................... 32 
6.1 
ASSESSMENT OF EFFICACY .............................................................................................. 32 
 
Primary efficacy variable ........................................................................................ 32 
 
Secondary efficacy variable ................................................................................... 32 
6.2 
ASSESSMENT OF SAFETY AND TOLERABILITY ...................................................................... 32 
 
Primary safety and tolerability variables ................................................................ 32 
 
Secondary safety and tolerability variables ........................................................... 33 
6.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................................... 33 
 
Baseline symptoms ................................................................................................ 34 
 
Definitions of Adverse Events ................................................................................ 34 
 
Follow-up of unresolved AEs ................................................................................. 37 
 
Reporting of adverse events .................................................................................. 37 
 
Reporting of suspected unexpected serious adverse reactions ............................ 38 
7 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT .......................................... 39 
7.1 
ESTIMATION OF SAMPLE SIZE ........................................................................................... 39 
7.2 
STUDY POPULATION ......................................................................................................... 39 
7.3 
METHOD OF IMPUTATION .................................................................................................. 39 
7.4 
METHOD OF STATISTICAL ANALYSES .................................................................................. 39 
 
Analyses addressing the primary objectives ......................................................... 40 
 
Analyses addressing the secondary objectives ..................................................... 41 
7.5 
DATA COLLECTION / CASE REPORT FORMS ....................................................................... 42 
7.6 
DATA MANAGEMENT ......................................................................................................... 43 
8 
REGULATORY AND ADMINISTRATIVE PROCEDURES .................................................. 43 
8.1 
INSTITUTIONAL REVIEW .................................................................................................... 43 
8.2 
SUBJECT INFORMATION / INFORMED CONSENT .................................................................. 44 
8.3 
SUBJECT CONFIDENTIALITY AND DATA PROTECTION .......................................................... 45 
 
Subject confidentiality ............................................................................................ 45 
 
Data Protection ...................................................................................................... 45 
8.4 
SUBJECT TREATMENT PLAN ............................................................................................. 45 
8.5 
GCP ............................................................................................................................... 46 
8.6 
ESSENTIAL DOCUMENTS ................................................................................................... 46 
8.7 
MONITORING / QUALITY CONTROL .................................................................................... 46 
8.8 
QUALITY ASSURANCE ....................................................................................................... 46 
8.9 
INSURANCE AND LIABILITY ................................................................................................ 46 
8.10 
END OF TRIAL .................................................................................................................. 47 
8.11 
STUDY REPORT ............................................................................................................... 47 
8.12 
PUBLICATION AND DATA RIGHTS ....................................................................................... 47 
9 
REFERENCES ...................................................................................................................... 49 
10 
SUMMARY OF PROTOCOL AMENDMENTS ...................................................................... 51 
11 
SIGNATURES ....................................................................................................................... 53 

 
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12 
SIGNATURE PAGE FOR INVESTIGATOR.......................................................................... 54 
13 
APPENDICES ....................................................................................................................... 55 
APPENDIX A ................................................................................................................................. 56 
APPENDIX B ................................................................................................................................. 57 
APPENDIX C ................................................................................................................................ 58 
APPENDIX D ................................................................................................................................ 59 
APPENDIX E ................................................................................................................................. 60 
 
 

 
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PROTOCOL OUTLINE 
Title of Study & 
Design 
PDC 01-0202: Open-label, prospective study to assess the safety, tolerability, analgesic effect, 
and feasibility of IN SUF/KET in pediatric patients with moderate or severe pain, in an acute 
care setting  
Study population  Pediatric participants from 1 year to <18 years inclusive. The aim will be to recruit the following 
minimum participants per age group: 
Age 1 - <5 years: 20 participants 
Age 5 - <9 years: 40 participants 
Age 9 - <18 years : 40 participants 
The remaining participants can be flexible enrolled.  
Number 
of 
patients 
150 pediatric participants evaluable for the primary endpoint  
Investigators/ 
Study Sites 
The study will be conducted at multiple sites in the Europe 
Diagnosis 
and 
Main Criteria for 
Inclusion 
Key inclusion criteria: 
- 
Pediatric participant, age 1 year to <18 years  
- 
Attending an Emergency Department (ED) following an injury 
- 
Acute pain of moderate or severe intensity (corresponding to 5 or above on an age-
appropriate pain scale (0-10 NRS, Wong-Baker FACES scale and FLACC pain 
scale) 
- 
Obtained informed consent by parent/guardian and assent from the child if possible 
and relevant (age dependent) 
Key exclusion criteria: 
- 
Participant showing abnormal nasal cavity/airway such as: 
- 
major septal deviation  
- 
evidence of previous nasal disease or surgery 
- 
current significant nasal congestion due to common cold 
- 
Has received treatment with sufentanil and/or ketamine during the last 72 hours 
- 
Known or suspected allergy to ketamine or sufentanil 
- 
Critical, life- or limb-threatening condition requiring immediate management   
Test 
Product, 
Dose and Mode 
of administration  
 
 
 
  
The dose may be repeated once after 10-15 min in case sufficient analgesia is not achieved 
after the first dose (i.e. pain intensity score >4/10 on age-appropriate pain scale per PI 
discretion).  
Duration 
of 
Treatment 
Patients will receive a single dose of CT001, with the option of a second dose after 10-15 min 
where sufficient analgesia is not achieved after first dose. Efficacy, safety monitoring, including 
measurement of vital signs will continue for 60 min. after the last dose or until rescue medication 
or procedures are initiated. 
Control(s)  
None   
 

 
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Primary Objectives 
Endpoints 
Assessments 
To assess the safety and 
tolerability of CT001 in pediatric 
participants with moderate to 
severe pain in an acute care 
setting 
The number and proportion (%) 
of participants with AEs 
Number of AEs, graded by 
severity, and number of SAEs. 
Pulse rate, 
Respiratory rate  
Peripheral oximetry 
Nasal irritation: (Combined participant and 
investigator reported nasal symptoms will 
be collected from all patients)  
Sedation: (The University of Michigan 
Sedation 
Scale 
(Malviya 
et 
al, 
Anesthesiology 2004) 
Unsolicited adverse events (incl CNS AE’s) 
 
 
To evaluate the analgesic effect 
of CT001 in pediatric participants 
with moderate to severe pain in 
an acute care setting  
Number and proportion (%) of 
participants that respond to the 
treatment relative to baseline 
(i.e. reduction in pain score to 4 
or below) at 15 min post IMP 
administration. 
Number and proportion (%) of 
participants that respond to the 
treatment relative to baseline 
(i.e. reduction in pain score to 4 
or below) within 30 min post IMP 
administration. 
 
Pain intensity score:  
For age group ≥ 1 year to < 5 years FLACC 
score (assessed by site staff).  
For age group ≥ 5 years up to 9 years visual 
analogue scale modified with Wong-Baker 
faces 
For age group 9 to < 18 years Numerical 
Rating Scale (NRS) 0-10. 
 
 
Secondary Objectives 
Endpoints 
Assessments 
To assess medication errors in 
pediatric 
participants 
with 
moderate to severe pain in an 
acute care setting 
Number of medication errors 
Type of medication errors (will be obtained 
via feedback from site staff that administer 
the IMP) 
To evaluate other analgesic effects 
of CT001 in pediatric participants 
with moderate to severe pain in an 
acute care setting  
Maximum 
change 
from 
baseline in pain intensity within 
30 min post IMP administration. 
 
Number and proportion of 
participants that achieve a 30% 
reduction 
in 
pain 
intensity 
relative to baseline within 30 
min post IMP. 
 
Change from baseline in pain 
intensity at 10, 15, 20, 30, 45 
and 60 min post IMP. 
 
Derived variables such as area 
under 
curve 
(AUC), 
peak 
change in pain intensity, and 
duration 
of 
effect 
will 
be 
calculated from the recorded 
pain assessments. 
Pain intensity score:  
For age group ≥ 1 year to < 5 years FLACC 
score (assessed by site staff). 
For age group ≥ 5 years up to 9 years visual 
analogue scale modified with Wong-Baker 
faces 
For age group 9 to < 18 years Numerical 
Rating Scale (NRS) 0-10.” 
To 
evaluate 
the 
need 
of 
supplemental analgesics.  
 
Number and proportion (%) of 
participants 
receiving 
additional analgesics. 
Time to the need for additional analgesics 
(will be obtained from the entire population)  
To evaluate feasibility of CT001 in 
pediatric participants with 
Average treatment satisfaction 
as assessed by respondents 
on a 5-point Likert scale 
A standardized question will be used: “How 
satisfied are you with the study drug that 
you/your child received? Please think 

 
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moderate to severe pain in an 
acute care setting 
about how it helped their pain, how it was 
given, any side effects, and how quickly 
you/your child recovered”. Respondents 
will answer using a 5-point Likert scale 
(very unsatisfied, unsatisfied, neutral, 
satisfied, very satisfied). Children that can 
orally give feedback will do so and for 
those that are too young, parent/guardian 
or site staff will provide input. 
Feasibility / Acceptance of 
nasal administration. 
Acceptance of the intranasal route of 
administration by asking the child: “If you 
were in this situation again and needed 
pain medication, would you like to receive 
the nasal spray?  If not possible by the 
child, then input will come from the 
parent/guardian. 
 
Statistical 
Methods  
General principles 
The primary objective of this study is to investigate the safety, tolerability and analgesic effects 
of CT001 in pediatric participants when used in an acute care setting. 
Data will be summarised using descriptive statistics. For continuous endpoints, the descriptive 
statistics include number of subjects, mean, median, standard deviation, standard error, lower 
and upper quartiles, minimum, and maximum. For categorical endpoints, frequency, and 
percentage will be given. Figures showing population distributions, such as box plots and 
histograms, will be reported for all applicable endpoints. The method of handling missing data 
for efficacy endpoints will be described for each set of endpoints. Missing data will not be 
imputed for safety endpoints. 
 
Sample size estimation 
So far, data from 375 children on IN sufentanil/ketamine show a safe and tolerable combination 
(data from PDC 01-0201, PDC 01-0203 and PDC 01-0206). Thus, from a safety perspective it 
is expected that 150 patients will be sufficient to capture and confirm the adverse event profile 
of the IMP.  
A formal sample size calculation was made for the primary efficacy endpoint on the basis of 
expecting a responder rate of 60%. A previous study reported a responder rate of 71.6 %, 
defined as pain intensity <= 3 at 30 min post IMP (16). With a sample of 113 patients, a one-
sample one-sided proportion design would provide at least 80% power to show that the 
responder rate is more than to 60%, with a significance level of 5%. Accounting for an 
approximate 25% dropout rate the resulting sample size is 150.  
Study populations 
The full analysis set (FAS) will consist of all patients who received at least one dose of study 
treatment (CT001). The FAS follows the intention-to-treat (ITT) principle, i.e. patients will be 
analysed regardless of whether treatment was received as planned. The FAS will be used for 
all analyses of primary and secondary safety and efficacy objectives. 
The FAS will be used to tabulate demographic data, baseline disease characteristics, and 
subject disposition.  
Statistical analysis of the primary endpoints 
The primary objective of the study will be evaluated using the FAS population. Data will 
further be evaluated by age group. 
Descriptive statistics will be used for safety variables.  Safety variables of special interest 
consist of vital signs, respiratory rate, pulse rate, oxygen saturation (SpO2), heart rate as well 
as sedation. 
Clinically significant out-of-range values and clinically significant relevant changes of values 
will be described descriptive statistics, number of subjects, number of events. 
Adverse events will be coded according to the MedDRA dictionary. The frequencies of 
adverse events will be tabulated by body system and “preferred term”. 

 
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The analgesic efficacy variable, responder rate (pain intensity of 4 or below at 15 min and 
within 30 min post IMP), will be reported using descriptive statistics.  
Statistical analysis of secondary endpoints 
All secondary endpoints will be analysed using descriptive statistics. Besides reporting 
summary descriptive statistics, Means and corresponding 90% symmetric confidence 
intervals estimated using the change from baseline in the respective variable unit. 
 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AUC 
Area Under Curve 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
DM 
Data Manager 
DPO 
Data Protection Officer 
EC 
Ethics Committee 
ED 
Emergency Department 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
The European Medicines Agency  
FAS 
Full Analysis Set 
FLACC 
Face, Legs, Activity, Cry, Consolability 
GCP 
Good Clinical Practice 
CHMP 
Committee for medicinal Products for Human Use 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IN 
Intranasal 
IQR 
Interquartile Range 
ITT 
Intention-To-Treat 
IV 
Intravenous 
KET 
Ketamine 
kg 
kilogram 
NRS 
Numerical Rating Scale 
mcg 
microgram 
min 
minute 
mg 
milligram 
mL 
millilitre 
PI 
Principal Investigator 
PIP 
Pediatric Investigational Plan 
PK 
Pharmacokinetic 
QP 
Qualified Person 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SmPC 
Summary of Product Characteristics 
SUF 
Sufentanil 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
UMSS 
University of Michigan Sedation Score 
 
 

 
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1 
INTRODUCTION 
1.1 
Background 
The proposed study aims to investigate the safety, tolerability, analgesic efficacy, and feasibility of 
intranasal (IN) sufentanil/ketamine (CT001) in pediatric participants attending an acute care (i.e. 
emergency) setting. The study is a part of the clinical development plan for the development of 
CT001 nasal spray for treatment of acute pain in children. The pediatric investigation plan (PIP) for 
CT001 nasal spray has been approved by the European Medicines Agency (EMA) in November 
2019 (EMA_001739-PIP02-16) (1). 
1.2 
Rationale for development of CT001 nasal spray  
Treatment of acute and procedural pain in children is characterized by frequent off-label use of 
pharmaceuticals with no evidence-based effect in the pediatric population, as well as 
pharmaceuticals with only a sedative effect, thus leaving the pain untreated. Despite the many pain-
relieving products available for adult patients, few of these have been developed for children and 
the treatment of acute pain in pediatric participants is characterized by a significant unmet medical 
need.  
IN drug administration for management of acute or procedural pain has several advantages over 
oral, rectal, or injectable drug formulations, including needle-free administration, easy to administer, 
rapid onset of therapeutic effect, and direct absorption to the systemic blood supply avoiding 
hepatic first-pass metabolism. IN administration is also applicable in situations where intravenous 
(IV) access for rescue analgesic treatment is not feasible or cannot be obtained e.g., in the 
prehospital setting or the emergency department (ED) setting. However, in most of the published 
studies of IN analgesia, commercially available drug preparations were used as nasal drops or non-
standardised sprays resulting in a dosing volume of up to several millilitres (mL’s) (2,3) potentially 
resulting in the swallowing of the drug and consequently gastrointestinal adverse events. Thus, a 
standardised pharmaceutical formulation is needed to ensure efficacious and safe analgesic 
treatment in the pediatric population. 
1.3 
Drug Class 
 
The active substances in CT001 are sufentanil citrate and ketamine hydrochloride, used in a fixed 
combination for IN use. From the Summary of Product Characteristics (SmPC), Sufentanil is 
authorized as a solution for IV or epidural injection (Sufenta) (4) and ketamine is authorized as a 
solution for injection (SmPC Ketamin Abcur) (5). However, no marketing authorization exists for the 
combination of sufentanil and ketamine as a nasal spray, consisting of a new pharmaceutical 
formulation.  

 
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Sufentanil and ketamine act at different central nervous system (CNS) sites (mu-opioid receptor 
agonist and N-methyl D-aspartate receptor antagonist, respectively). Sufentanil’s mechanism of 
action is like other opioids, and it has an analgesic effect and a dose-dependent sedative effect.  
Ketamine has a dose-pendent action as a general anaesthetic agent producing an anaesthetic 
state termed “dissociative anaesthesia” characterized by profound analgesia. Ketamine has an 
analgesic effect at sub-anaesthetic plasma concentrations. Psychotomimetic side effects including 
hallucinations, abnormal dreams, nightmares, confusion, and abnormal behaviour occur commonly 
(≥1/100 to <1/10 patients) with anesthetic doses of ketamine (5). However, perioperative use of 
injectable ketamine in children in sub-anesthetic/analgesic doses (median 0.5 mg/kg) has not been 
associated with psychomimetic side effects (6). The dose of ketamine in CT001 is equivalent to low 
analgesic doses. 
The fixed combination of IN sufentanil and ketamine may provide an additive analgesic effect (also 
referred to as balanced analgesia). Thus, lower doses of sufentanil and ketamine may be needed 
to achieve adequate analgesia (relative to sufentanil alone) resulting in potentially fewer adverse 
events (AEs).  
1.4 
Previous Non-clinical and Clinical Studies 
 Non-Clinical Studies 
The nonclinical profile of CT001 (fixed medicinal product containing the two active ingredients 
sufentanil and ketamine) is based on bibliographical research on safety and toxicity data for 
sufentanil, ketamine and the free combination of the two active ingredients. For further information 
see the current Investigator’s Brochure, version 5.0. 
No further non-clinical studies will be conducted as agreed at a Scientific Advice with CHMP at the 
European Medicines Agency (EMEA/H/SA/3623/1/2017/PED/II) and in the approved pediatric 
investigation plan (1).   
 Clinical studies 
There is currently extensive clinical experience with both ketamine and sufentanil. Sufentanil is 
marketed in several EU Member States as solution for IV or epidural injection. Sufentanil was first 
approved in Belgium and Luxemburg in 1978 (4). Sufentanil is approved for adults and children 
above 1 month for maintenance of anaesthesia, for epidural analgesia in adults including epidural 
analgesia during labour and delivery and epidural analgesia in children above 1 year. Ketamine is 
marketed in several EU Member States. Ketamine was first approved by the Food and Drug 
Administration in 1970 as a solution for injection. Ketamine and its enantiomer s-ketamine are 
approved for adults and children (no age specified) for induction of anesthesia, analgesic 
supplement in regional and local analgesia and analgesia in acute situations. In general, IV opioids 
(e.g. sufentanil) and ketamine are used in combination for different analgesic regimes as ketamine 
has been indicated to potentiate the analgesic effect of opioids (5,7). Thus, sufficient analgesia may 

 
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be achieved with a lower dose of opioid when combined with ketamine than with opioid 
monotherapy, thereby reducing the risk of opioid-related adverse events, including respiratory 
depression.  
CT001 has been investigated in several clinical studies. The doses of IN sufentanil and ketamine 
were based on wide clinical experience from off-label use of commercially available solutions 
administered as nasal drops (8,9). 
 
 
 
 
Heart rate and oxygen saturation were stable, and sedation was minimal. No serious adverse 
events (SAEs) were reported.  
Bibliographic data of IV sufentanil and ketamine has indicated that for children out of infancy 
(approx. >2 years) pharmacokinetics of sufentanil and ketamine are well described using allometric 
models.  Investigation of absolute bioavailability of IN administration is challenging in the pediatric 
population and absolute bioavailability of the IN sufentanil/ketamine fixed combination in adults has 
been conducted in a separate PK bridging study (PDC01-0204) using the proposed administration 
device. The study included 15 healthy volunteers in a cross-over study design where 14 received 
intranasal 27 microg sufentanil / 27 mg ketamine, 15 subjects received 10 mg ketamine 
intravenously and 14 subjects received 10 microg sufentanil IV. The estimated bioavailability for 
sufentanil and ketamine was 39% and 47%, respectively.  
 
For an overview of published studies of IN sufentanil and IN ketamine/s-ketamine and IN 
sufentanil/ketamine/s-ketamine combinations please refer to the current Investigator’s Brochure, 
version 5, which includes data from both published studies and clinical experience of more than 
700 children that have received IN sufentanil or ketamine/s-ketamine or combinations of sufentanil 
and ketamine/s-ketamine. 
1.5 
Ongoing Clinical Study with CT001 
 
One phase II study is currently ongoing with CT001. The primary objectives for the PDC01-0205 
study are to investigate the analgesic effect and the concentration-effect relationship 
(pharmacokinetic-pharmacodynamic relationship) across different IN doses of sufentanil, ketamine 
and CT001 (sufentanil/ketamine fixed combination) for the treatment of acute postoperative pain in 
adults undergoing removal of an impacted mandibular third molar.  

 
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1.6 
Rationale of the Present Study 
This open-label prospective study aims to investigate the safety, tolerability, analgesic efficacy, and 
feasibility of one or two repeated doses of IN sufentanil/ketamine in pediatric participants aged 1-
17 years (inclusive), suffering from moderate to severe pain while being in an acute care setting. 
The pharmacological rationale of the CT001 is a multimodal (balanced) analgesic treatment 
combining low-dose sufentanil and low-dose ketamine providing analgesic plasma concentrations 
with concomitant reduced risk of opioid-related side effects, including respiratory depression. 
This phase II study is the last study as part of the clinical development plan for the development of 
sufentanil/ketamine nasal spray for treatment of acute and procedural pain in children. The pediatric 
investigation plan (PIP) for sufentanil/ketamine nasal spray has been approved by the European 
Medicines Agency in November 2019 (EMA_001739-PIP02-16) (1).  
1.7 
Ethical Considerations 
 Risk and inconveniences to the patients 
Acute pain of moderate to severe intensity is common in children in the acute care (i.e. emergency) 
setting.  In most cases oral treatments do not provide sufficiently rapid analgesia. Intramuscular 
and subcutaneous injections are also slow-acting, as well as being painful when administered. A 
fast titration of an effective dose within a reasonable time is also not possible. Thus, standard-of-
care to date to manage acute moderate to severe pain is mainly off-label IN opioids. The IN route 
of administration has been well accepted in clinics and acute care settings by both children, parents, 
and healthcare staff due to its low invasiveness and high effectiveness. 
The IMP CT001 will be administered intranasally. Both sufentanil and ketamine are well-known 
drugs for the treatment of acute pain (9). The doses of the IMP (CT001) have previously been 
shown to be effective in a clinical setting in children for procedural pain management (10). 
Common dose-dependent side effects of sufentanil are nausea, vomiting, itching and sedation (1-
≥10%) (4). While for IV ketamine (in sub-anesthetic doses used for analgesia), sedation and 
nausea/vomiting are common side effects (5). In the completed pediatric study (PDC 01-0201, 
EudraCT 2009-013801-33) investigating the IN combination of sufentanil and ketamine unpleasant 
taste, vomiting and dizziness were the most common adverse events, see Investigators Brochure, 
version 5.   
Study medication will be administered on one occasion, with the possibility of adding a second dose 
if the first dose did not result in sufficient pain relief as per investigator discretion. Pain intensity will 
be assessed using age-relevant pain intensity scoring scales.  
During and following IN administration of the combination of study drug, non-invasive assessments 
of heart rate, oxygen saturation and respiratory rate will be done. A physician will be present when 
the IMP is administered in case of potential side effects requiring any additional treatment. During 
the study participation, the child and parent/legal guardian will be queried for subjective adverse 

 
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events. Furthermore, the study will focus on assessment of nasal tolerability to ensure that the IMP 
is not associated with local irritation of the nasal mucosa. Patients will be asked specific questions 
related to nasal tolerability. 
 
 Euphoria and psychological dependency 
A well-known, serious adverse effect of exposure to opioids is the potential development of 
addictive behaviour i.e., a biopsychosocial determined motivational phenomenon including strong 
and compulsive, rewarding and reinforcing experiences. Experiencing opioid-induced euphoria, 
even during a short-lasting exposure, unfortunately, may lead to a state of addiction and 
psychological dependency. Since 2016, in the context of the "opioid epidemic" in the U.S., a high 
prevalence of persistent post-surgical use of opioids has been identified in previous opioid-naïve 
patients (11–13).  It is not known how much of the prevalence (3-7%) from the post-surgical 
population that reflects persistent post-surgical pain state or a psychological dependency.  
 
However, continued opioid prescription for more than three months following a post-surgical 
scenario, cannot be rightfully extrapolated to the present experimental scenario with one or 
maximum two administrations, i.e., only a short exposure time to sufentanil. Consequently, the risk 
for patients to become dependent or experience euphoria after being part of this study is considered 
minimal. 
1.8 Benefit-Risk Assessment 
Patients who present to an ED suffering from moderate or severe acute pain following an isolated 
injury will be approached for recruitment. In the context of this study, an isolated injury refer to “a 
non-critical and non-limb threatening physical wound or injury of the tissues”, including (but not 
limited to) closed fractures of the extremities, joint dislocations, joint sprains, burns and scalds, soft 
tissue lacerations, and penetration by foreign bodies. 
After obtaining informed consent from an accompanying parent/legal guardian (or from competent 
16- and 17-year-old patients is accepted per local regulations) +/- assent from the child (per local 
regulations), the child will receive study treatment according to the study protocol. There is no 
placebo group in the study and the open-label study design will minimize any untoward delay in 
receiving acute pain relief. The patients are expected to have a direct benefit of CT001.  
Standard of care for acute pain management in an emergency setting already includes IN or IV 
opioids. However, when used as IV injection, it requires the insertion of an IV cannula before pain 
treatment can be administered. This procedure may be painful and, in an emergency setting, also 
challenging for the nurse or doctor conducting the insertion. Current use of IN opioid administration 
is frequently performed using commercially available IV opioids preparations using a mucosal 
atomization device. This approach may require up to several milliliters of drug (depending on weight 

 
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of the child) causing possibly swallowing of the drug and consequently gastrointestinal adverse 
events. There is less risk of this with CT001 as the volume required will be much less (See IMP 
section for more details).  
For the investigational product (IMP, CT001) the doses are comparable to the doses used as 
premedication before anesthesia in opioid-naïve patients and administration is not expected to be 
associated with substantial risk or unknown adverse events. Administration of opioids like sufentanil 
may cause mild side effects like nausea/vomiting, sedation and itching in some patients, regardless 
of the dose. The children and their parents/legal guardians will be well-informed (age adjusted) 
about receiving an opioid in this trial. The potential benefit for the pediatric population of the easy 
to administer, analgesic treatment, is considered to outweigh the expected low risk in these 
patients. 
 Pregnancy and acute opioid and ketamine use 
Limited amount of data exists from the use of sufentanil and ketamine during pregnancy. Sufentanil 
and ketamine crosses the placenta. There are, however, no indications to date that the use of 
sufentanil during pregnancy increases the risk of congenital abnormalities. The risk to the fetus can 
depend on various factors such as the gestational age of the pregnancy, dosage and duration of 
sufentanil and ketamine use.  
In the current study CT001 will be used for acute pain management only and the duration of 
sufentanil and ketamine exposure will be very limited. Known pregnancy is a protocol exclusion 
criterion and the site staff will ask female participants that have reached menarche if they may be 
pregnant (and thus excluded). For ethical reasons it is not feasible in the ED setting to perform 
urine or serum pregnancy test as this would significantly delay the time to analgesia for patients  in 
moderate to severe pain.  
 

 
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2 
OBJECTIVES 
Primary objectives:  
• 
To assess the safety and tolerability of CT001 in pediatric participants with moderate 
to severe pain in an acute care setting 
• 
To evaluate the analgesic effect of CT001 in pediatric participants with moderate to 
severe pain in an acute care setting 
 
Secondary objectives:  
• 
To assess medication errors in pediatric participants with moderate to severe pain in 
an acute care setting. (To be provided by site staff administering the IMP)  
• 
To evaluate other analgesic effect of CT001 in pediatric participants with moderate to 
severe pain in an acute care setting. 
• 
To evaluate the need of supplemental analgesics.  
• 
To evaluate feasibility of CT001 in pediatric participants with moderate to severe pain 
in an acute care setting. 
3 
POPULATION 
 
The study population will be recruited from children and young people aged 1 – <18 years (prior to 
their 18th birthday), who present to an ED following an isolated injury where immediate pain relief 
is judged to be needed.  
3.1 Inclusion Criteria 
To participate in the study, and prior to performing any study-related procedures, the following 
inclusion criteria must all be met:  
1. Participant aged 1 to <18 years. 
2. Attending an ED following an injury. 
3. A pain intensity score corresponding to moderate or severe pain, as assessed by age relevant 
scales:  
• 
Age group ≥9 to <18 years: pain score 5 to 10 using the Numerical Rating Scale (NRS); 
self-reporting by the participant. 
• 
Age group ≥5 to <9 years: pain score 6 to 10 using the Wong-Baker FACES scale; self-
reporting by the participant. 
• 
Age group ≥1 to <5 years: pain score 5 to 10 using the FLACC pain scale; assessed by 
site staff. 
4. Evidence of signed and dated informed consent form, indicating that the participant and/or 
parent/ guardian (if participant younger than 16 years) has been informed of and has fully 
understood all pertinent aspects of the study as required for the age of the child in accordance 
with local legislation.  

 
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3.2 Exclusion Criteria 
To participate in the study potential participants must not meet any of the following exclusion 
criteria: 
 
1. Critical, life- or limb-threatening condition requiring immediate management. 
2. Open fractures. 
3. Participants with chronic pain. 
4. Participants requiring oxygen therapy. 
5. Clinically evident respiratory depression. 
6. Clinically evident cardiovascular instability (e.g. pathological arrhythmia). 
7. Known liver disease. 
8. Known kidney disease. 
9. Presence of other acute clinical or medical condition that may, in the opinion of the 
investigator, put the potential subject at risk when participating in the study, impact the 
participant’s ability to participate in the study, or have impact on the study results, including 
being subject to head injury and / or altered consciousness.  
10. A female of childbearing potential is eligible to participate if she verbally confirms not to be 
at risk of being pregnant or breastfeeding and agrees to follow the contraceptive guidance 
for 7 days after IMP administration. 
11. Acute intoxication with drugs or alcohol, based on the judgement of the attending physician. 
12. Participant showing abnormal nasal cavity/airway such as: 
a. major septal deviation  
b. evidence of previous nasal disease or surgery 
c. current significant nasal congestion due to common cold 
13. History or presence of hypersensitivity or allergy to sufentanil or ketamine, a history of 
anaphylactic reactions, or a history of other allergy that, in the opinion of the investigator, 
contraindicates their participation. 
14. Has received treatment with sufentanil and/or ketamine during the last 72 hours 
15. Is currently participating in or has participated in an interventional clinical trial with an 
investigational compound or device in the 4 weeks prior to signing the informed 
consent/assent for this trial.  
16. Previous enrolment in the present study. 
 
3.3 Recruitment and Screening 
Participants will be identified and recruited from the ED. The participant-targeted recruitment 
initiatives and any information given to potential participants and/or their parents or legal guardians 
will be submitted to, and approved by, the respective Ethics Committee(s) prior to implementation.   
 
The Investigator is responsible for obtaining informed consent and assent (in accordance with local 
regulations), please see section 8.2. Information about the study may explained to the participant 
and parent/guardian by an experienced study nurse but the consent should be obtained by the 
investigator.  
 
During the screening assessment, a participant ID number will be assigned for identification of the 
participants. The Investigator will maintain a participant ID Log for all participants who undergo 

 
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screening. If assessments required for screening have already been completed as part of standard 
treatment at the ED prior to participant/parent/guardian signing the ICF, historical data can be 
collected, see section 4.2.  
 
After completion of screening (part 1), all participants deemed eligible to take part in this study will 
be enrolled. If a participant screen fails, this will be noted in a screen failure form. 
 
 Pregnancy and contraceptive guidance 
 
Females that have reached menarche, will be excluded if they verbally state any possibility of  being 
pregnant or  if they are breastfeeding.  
 
Eligible females that have reached menarche must use contraception for 7 days after IMP 
administration. Acceptable contraceptive methods include: 
- 
Sexual abstinence 
- 
Combined hormonal (estrogen and progesterone) contraception associated with inhibition 
of ovulation (oral, intravaginal or transdermal) 
- 
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable) 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS) 
- 
Bilateral tubal occlusion 
- 
Vasectomized partner 
 
3.4 Lifestyle considerations 
 Meals and dietary restrictions 
Not applicable in an emergency setting. However, the time of last oral intake (fluids and solids) will 
be documented. 
 Activity restrictions 
Ambulation is allowed between drug administration and any indicated medical procedures.  
 Driving and bicycling 
Participants will be told not to engage in critical complex personal decisions, or operate heavy 
machinery, car driving or riding a bicycle on the day of the IMP administration. 
 

 
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4 
STUDY PROCEDURES 
4.1 
Overall Study Design 
 
This study is an open label multi-centre study evaluating the safety, tolerability, analgesic efficacy, 
and feasibility of IN CT001, on acute pain relief in pediatric participants in an acute care setting 
where acute pain relief is judged to be needed. The study comprises of 2 study parts on Day 1, and 
part 3 consisting of a follow up phone call (on Day 2-7). On Day 1, participants will be screened 
(Part 1), enrolled and treated (Part 2). For the overall study design, see Figure 1. 
 
 
Figure 1. Schematic Study Design,  
ED; emergency department, IMP; investigational medicinal product. 
 
Children and young people attending an ED who report moderate or severe pain will be eligible for 
enrolment in the study. In total, 150 evaluable participants will be included, with an estimated need 
to screen 180 subjects to reach the necessary number of evaluable patients. Each participant will 
receive one or potentially two consecutive doses of intranasally administered CT001 (with 10-15 
min in-between).  
All study related activities will take place in the acute care setting, including monitoring of vital signs 
(measurements of pulse rate, oxygen saturation and respiratory rate). The participating EDs will all 
contain appropriate equipment and drugs to address any complications from the trial medication, 
including standard airway/breathing life support equipment, rescue analgesia, and naloxone. 
 
 
 
 
 
 

 
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4.2 Clinic visits 
 
Part 1; Screening (Day 1) 
Potentially-eligible participants and their parents or legal guardian will be provided with written 
information about the study. Families who state an interest in participation will be asked to provide 
written informed consent +/- assent, as appropriate for the age group in accordance with local 
legislation. A patient ID number will then be assigned. 
 
Following completion of the informed consent form (ICF), a formal screening assessment will be 
conducted, including assessment of eligibility according to the study inclusion and exclusion 
criteria. Pain scoring within the screening assessment will be conducted using the following pain 
intensity scores: 
 
Age ≥9 years:  
A 0-10 numerical rating scale (NRS) scale (10).  
Age ≥5 to <9 years:  
The Wong-Bake FACES scale (14).  
Age ≥1 to <5 years:  
The FLACC scale (15). 
 
The same pain scale will be used for all subsequent study pain scores for that patient. 
 
Any preceding data from the routine ED triage assessment (such as demographics, injury type, 
pain score, concomitant medications, and vital signs) can be utilized and transferred onto the 
screening electronic Case Report Form (eCRF). 
 
The screening assessment will also include documentation of participant demographics, past 
medical history, and concomitant medications. If not already undertaken at the routine triage 
assessment, the participant will be weighed. Where a participant’s injury makes weighing 
impractical, an estimated weight will be documented.  
 
Females participants that have reached menarche, will be asked if it is any possibility tht thy could 
be pregnant. If they respond yes, they will not be eligible for the study. Females participants that 
have reached menarche and who are sexually active will be asked to follow contraceptive guidance 
for 7 days following IMP administration. 
 
For further guidance on assessments at screening, see Study Assessment Chart Table 1. 
 
Part 2; Baseline and IMP treatment (Day 1) 
The baseline assessment will include a repeat pain score, sedation score, and measurement of the 
participant’s vital signs (respiratory rate, pulse rate, oxygen saturation) if not already undertaken at 

 
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the routine triage assessment. Once the pre-treatment assessments are performed the IMP will be 
administered.   
 
After administration of IMP, pain scores will be assessed at the following approximate intervals (10, 
15, 20, 30, 45, 60 min post IMP), as specified in the Study Assessment Chart (Table 1). The actual 
timepoints for pain assessment relative to IMP administration will be recorded in the eCRF. 
 
Unscheduled pain intensity scores will be measured and documented during any potentially painful 
intervention (e.g. during the application of a plaster cast for a fracture), prior to rescue medication 
or prior to premature study withdrawal. 
 
Where pain relief at 10-15 min after the first IMP administration is insufficient (for example, a pain 
score >4/10 on NRS, or at the discretion of the treating investigator), a second IMP dose of similar 
strength and dose can be administered to the participant. In the case of insufficient pain relief after 
two doses of IMP, additional analgesic medication may be administered at the discretion of the 
treating investigator, in accordance with standard local practice. The medication, dose and time of 
administration will be recorded in the eCRF.  
 
After administration of IMP, level of sedation, vital signs (pulse rate, peripheral oxygen saturation, 
respiratory rate), nasal tolerability and spontaneously reported adverse events will be assessed.  
 
Pain scores and safety assessments should continue for 60 min after the last dose of IMP, or until 
additional analgesic treatment or procedures need to be initiated. For further guidance on 
assessments at the treatment and post-treatment visit (Part 2), see Study Assessment Chart, Table 
1. 
Feasibility and treatment satisfaction in relation to the IMP and route of administration will be 
assessed prior to ED discharge.  
 
Treatment satisfaction will be addressed by using the following standardized question: “How 
satisfied are you with the study drug that you/your child received? Please think about how it helped 
their pain, how it was given, any side effects, and how quickly you/your child recovered”. 
Respondents will answer using a 5-point Likert scale (very unsatisfied, unsatisfied, neutral, 
satisfied, very satisfied).  
 
Acceptance of the intranasal route of administration will be assessed by the child. The healthcare 
professional will ask the child: “If you were in this situation again and needed pain medication, 
would you like to receive the nasal spray (relative to getting an injection, tablet or suppositories for 
the pain)? If not possible by the child, then by the parent/guardian. 

 
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Part 3; Text/telephonic follow-up for safety (Day 2-7) 
On day 2-7 the parent/legal guardian (or patient if aged 16 to <18) will be contacted via text 
message (if possible), asking if the patient has experienced any side effects following discharge 
from the ED. If the reply is “yes” or the person does not respond to the text, the site investigator will 
attempt to contact them by phone to obtain further information about these adverse events. A total 
of 3 attempts will be made to make telephone contact. If all attempts are unsuccessful, the patient’s 
General Practitioner (GP) may be contacted for any relevant follow-up information. For further 
guidance on assessments, see Study Assessment Chart in Table 1. 
 
 
 
 

 
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and needed pain medication, would you like to receive the nasal spray? If not possible by the child, the 
parent/legal guardian will assess nasal acceptability.  
g) 
Any medication given for AEs during the time from enrolment to follow up should be entered in the 
eCRF. Any ‘rescue medication’ (described as additional analgesics due to insufficient effect of IMP 
during the 60 min after the last dose of IMP), should be entered in the eCRF. The time given should 
also be noted. 
4.3 
Assessments 
Assessment results will be recorded in the eCRF, as applicable. 
 Medical and surgical history  
A verbal medical and surgical history will be collected from the participant/legal guardian as part of 
admission procedures and recorded as historical data in the source notes and eCRF. Medical 
history will not be verified by referring to existing participant notes or by contacting the participant’s 
General Practitioner, for example. Due to the acute nature of this protocol in an ED setting, the 
scope of the exclusion criteria, the short duration of the participant within the study and the short 
acting nature of the IMP, verification of medical history is not reasonably practical. 
 Pain intensity assessments  
The pain resulting from injury causing the emergency visit will be quantified. The participant will be 
introduced to the age-appropriate pain scale and overall pain will be assessed, with no distinction 
made between spontaneous pain and any procedural pain.  
 
Immediately prior to administration of the IMP (baseline), the pain intensity will be rated using the 
applicable tool (see below). Subsequent pain assessments will be performed at 10, 15, 20, 30, 45, 
and 60 min post IMP administration. If a second dose of IMP is administered after 10-15 min, the 
pain assessment schedule will be reset, and pain will be measured at 10, 15, 20, 30, 45, and 60 
min after the second dose of IMP, or until additional analgesics or procedures needs to be initiated.  
Unscheduled pain intensity scores will be measured and recorded during any potentially painful 
intervention (e.g. during the application of a plaster cast for a fracture), prior to rescue medication 
or prior to premature study withdrawal. 
Age-appropriate pain intensity assessment tools will be used:  
 
Age ≥9 years: The Numerical Rating Scale (NRS) will be used. The NRS scales consists of a Likert 
scale, anchored with numbers 0-10, with 0 marked “No pain” and the right end (10) marked “Worst 
pain imaginable”. The patient will state the number representing their current level of pain, and the 
study staff will circle the applicable number on the CRF page (see Appendix A). 
 

 
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Age ≥5 to <9 years:  The visual analogue scale modified with six faces developed by Wong-Baker 
(Wong-Baker FACES pain rating scale) will be used. Numerical values (0, 2, 4, 6, 8, 10) are listed 
for each face (Wong et al, 2001, see Appendix B). 
 
Age 1 to <5 years: The study investigator will provide an assessment of pain, using the FLACC 
scale (Merkel et al, 1997, see Appendix C).  
 
 
 Assessment of sedation 
The level of sedation will be assessed using the University of Michigan Sedation Score (UMSS, 
Appendix D). The UMSS has been validated for the assessment of procedural sedation in children. 
Level of sedation will be assessed at baseline (i.e. pre-IMP administration) and at 10, 15, 20, 30, 
45, and 60 min post IMP immediately following each pain assessment. If a second dose of IMP is 
needed the sedation score will be performed at the same time points relative to the second dose. 
 Vital signs 
The following vital signs will be measured at baseline and post IMP administration and recorded in 
the eCRF:  
- 
Pulse rate (bpm): will be recorded from the pulse oximeter. 
- 
Blood oxygen saturation (%), assessed by pulse oximetry (non-invasive method). 
- 
Respiratory rate (breaths per minute).  
The vital signs will be measured immediately after the pain and sedation assessments, at the same 
times points, i.e. at 10, 15, 20, 30, 45, and 60 min post IMP, or until additional analgesics or 
procedures needs to be initiated. If values are not within normal range after 1-hour, vital sign 
measurements can be continued until ED discharge or until additional procedures need to be 
initiated.  
 Assessment of the nasal tolerability 
Nasal tolerability/irritation will be assessed for all patients based on combined participant reported 
symptoms and investigator examination/inspection of the nasal cavities. The symptoms and signs 
can include sneezing, redness, itching, nasal discharge, local tenderness, swelling or other nasal 
irritation. Nasal tolerability/irritation will be assessed at 30- and 60-min post IMP administration 
(following pain, sedation and vital sign assessments). The 30 and 60 minute nasal tolerability 
timepoints should be taken from the last dose of IMP i.e. if a second dose of IMP is required, nasal 
tolerability should then be performed 30 and 60 minutes from the second dose. Any unpleasant 
symptoms from the nose during or after administration of the IMP reported by the participant will 
be recorded as adverse events. 

 
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 Assessment of medication errors 
Medication errors will be assessed by feedback from site staff that administer the IMP. If they eg 
do not switch between nostrils when dosing CT001, or give a different number of sprays than 
required per IMP manual. 
 Need for additional analgesics 
In the case of insufficient pain relief after two doses of IMP, additional analgesic medication may 
be administered at the discretion of the treating investigator, in accordance with standard local 
practice. The type of rescue medication, dose and time of administration will be recorded in the 
eCRF. If a participant is given additional analgesics during the study, the pain assessments after 
administration of rescue medication will not be included in the efficacy analyses. This will be further 
described in the statistical analysis plan.  
 Demographics and weight 
 
The bodyweight (in kg) of the participant will be measured during screening. Where a patient’s 
injury makes weighing impractical, an estimated weight will be documented. Recording of 
demographics (sex, date of birth, ethnicity) will also be performed during screening. 
 Adverse events 
See section 6.3 Adverse Events and Serious Adverse Events. 
 Concomitant medication 
The following medications will be reported: 
• 
Prescription medications within the previous 7 days. 
• 
Over-the-counter medications within the previous 24 hours. 
• 
IN medications within the previous 48 hours.  
  
 Any medication given for AEs during the time from enrolment to follow up should be entered 
in the eCRF. Any ‘rescue medication’ (described as additional analgesics due to insufficient 
effect of IMP during the 60 min after the last dose of IMP), should be entered in the eCRF. The 
time given should also be noted.Feasibility / Treatment satisfaction 
Feasibility / treatment satisfaction in relation to the IMP and route of administration will be assessed 
prior to ED discharge.  
 
Treatment satisfaction will be addressed using the following standardized question: “How satisfied 
are you with the study drug that you/your child received? Please think about how it helped their 

 
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pain, how it was given, any side effects, and how quickly you/your child recovered”. Respondents 
will answer using a 5-point Likert scale (very unsatisfied, unsatisfied, neutral, satisfied, very 
satisfied).  
 
Feasibility (i.e. acceptance of nasal administration) will be addressed by the healthcare staff asking 
the child: If you were in this situation again and needed pain medication, would you like to receive 
the nasal spray (relative to an injection, tablet or suppository for the pain)? If not possible by the 
child, the parent/legal guardian will assess nasal acceptability. Answers will be “yes”, “no”, “I don’t 
know”. If not possible by the child, then the parent/guardian.  
 
 Text/telephonic follow-up for safety 
On day 2-7 the parent/legal guardian (or patient if aged 16 to <18 if in accordance with local 
legislation) will be contacted via text message, asking if the patient has experienced any side effects 
following discharge from the ED. If the reply is “yes” or the person does not respond to the text, the 
site investigator will attempt to contact them by phone to obtain further information about these 
adverse events. A total of 3 attempts will be made to make telephone contact. If all attempts are 
unsuccessful, the patient’s General Practitioner (GP) may be contacted for any relevant follow-up 
information. The patient/ legal guardian(s) may, at any time during the study, contact the Principal 
Investigator, to discuss any drug experiences if needed. If it is not possible to reach the parent/legal 
guardian or the GP for the follow up phone call (on Day 2-7), then it should be stated that the patient 
is lost to follow up. 
4.4 Participant Withdrawal 
The Investigator will explain to the participant and legal guardian that they have the right to withdraw 
from the study at any time, and that this will not prejudice any future treatment. A participant who 
has consented to the study but not yet received IMP will be considered a screen failure if they 
decide to withdraw consent prior to receiving IMP. Once a participant has been administered IMP 
and subsequently decides to withdraw consent, the participant would be considered withdrawn. 
The reason for any kind of withdrawal must be recorded in the eCRF. 
 
Reasons for withdrawing from may be: 
• 
Unacceptable adverse events 
• 
Participant or guardian’s request 
• 
Investigator's discretion 
• 
Intercurrent illness 
 
 

 
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Whenever a participant is withdrawn from the study, the reason(s) of why the participant was 
withdrawn from the study should be recorded. All documentation concerning the participant must 
be as complete as possible, however, no new information can be collected if the participant or legal 
guardian has withdrawn his/her consent/assent to further study participation. 
4.5 Replacement of participants 
In total, 150 evaluable participants will be included and exposed to IMP. If a participant/legal 
guardian withdraws his/ her consent prior to IMP dosing, he/ she will be replaced. If a participant is 
withdrawn due to technical reasons or due to a surgical unrelated medical complication, he/ she 
will be replaced. 
Rescreening of participants will not be allowed.  
 
5 INVESTIGATIONAL MEDICINAL PRODUCT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 

 
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The handling and storage will be further detailed in the IMP manual. 
The IMP will be stored at room temperature (2-25 °C) at the study site in a secure area (a locked 
cabinet or drug storage room), protected from unintended use. A temperature log will be kept.  
IMPs will be labelled according to local requirements. 
 Non-investigational medicinal products (NIMPs) 
 
Rescue medication  
Rescue medication can be given on the discretion of the investigator at any time in case of 
insufficient pain relief of IMP. Rescue medication should be given in accordance with local clinical 
practice. The type of rescue medication, dose and time of administration will be recorded in the 
eCRF.  
5.2 Supply, Packaging, Labelling, Handling and Storage 
The IMP will be manufactured, packaged, study labelled, batch certified by a qualified person (QP), 
and distributed in accordance with the principles of Good Manufacturing Practice and Good 
Distribution Practice, under the responsibility of Cessatech (or its designee).  
IMP is prepared for dosing according to instructions. Detailed instructions for the preparation and 
handling of IMP will be provided by sponsor.  
The wording on the participant-specific labels will be in accordance with Good Manufacturing 
Practice regarding labelling and national and/or local regulatory requirements. 
5.3 Dosage and Administration 
Dosing of CT001 in children is presented in mcg/kg (SUF) and mg/kg (KET). 
 
 
 
 
 
to allow for simple 
dosing instructions while keeping an adequately narrow dose range around the target dose. This 
approach and the below dosing chart (Table 2) have been endorsed by the EMA. 
The below dosing table described one dose administration, which then can be repeated once after 
10-15 min, in the case of insufficient pain relief. Actuations should be given in alternating nostrils. 
 
 

 
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 The dose administration is also be described in a separate IMP 
manual. 
5.4 Number of Participants Treated in Different Age Groups 
Participants from 1 to <18 years of age (inclusive) will be enrolled into the study. The aim will be to 
enrol the following minimum number of participants in each age group: 
 
Age 1 - <5 years: 20 participants 
Age 5 - <9 years: 40 participants 
Age 9 - <18 years (inclusive): 40 participants 
 
The remaining 50 participants can be flexibly enrolled into the age groups. Deviations to the above 
numbers may be accepted in case of recruitment challenges in some age groups.   
5.5 IMP Accountability 
All IMP for this study must be always retained in a safe place. Only personnel authorised by the PI 
at the site should dispense and administer the IMP. The investigator or pharmacist must complete 
an IMP accountability log, documenting product dispensed and used. This will be verified by the 
study monitor prior to destruction. Remaining IMP will be sent for destruction at the local hospital 
pharmacy, and this will be documented with a destruction certificate. If local pharmacy cannot 
destroy IMP, it can be returned for destruction according to the IMP manual.   
 

 
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6 RESPONSE VARIABLES AND ENDPOINTS  
6.1 
Assessment of Efficacy 
 Primary efficacy variable 
To investigate the analgesic efficacy of IN CT001 in pediatric participants in the acute care setting 
experiencing pain of moderate to severe intensity. 
• 
Analgesic efficacy will be assessed as changes in pain intensity from baseline using age 
relevant scoring instruments (FLACC score for ages ≥ 1 year to < 5 years, the Wong-Baker 
faces scale from ages ≥ 5 years to < 9 years, and the 0-10 Numerical Rating Scale (NRS) 
from ages 9 and above). The pain assessments will be made prior to the first IMP dose 
(baseline) and then at the following timepoints: at 10, 15, 20, 30, 45, 60 min post first IMP 
dose. The primary efficacy endpoints will be the responder rate i.e., the percentage of 
participants that has a pain intensity score at 4 or below at 15 min and at any timepoint 
during 30 min post IMP. 
 
Secondary efficacy variable 
To evaluate additional analgesic effect of CT001 in pediatric participants with moderate to severe 
pain in an acute care setting  
• 
Maximum change from baseline in pain intensity within 30 min post IMP administration. 
• 
Number and proportion of participants that achieve a 30% reduction in pain intensity 
relative to baseline within 30 min post IMP. 
• 
Change from baseline in pain intensity at 10, 15, 20, 30, 45 and 60 min post IMP. 
• 
Derived variables such as area under curve (AUC), peak change in pain intensity from 
baseline, and duration of effect will be calculated from the recorded pain assessments. 
 
To evaluate the need for supplemental analgesic medication during the study period 
• 
Number and proportion of children receiving additional analgesics, as assessed by 
timepoint. 
6.2 Assessment of safety and tolerability 
 
 Primary safety and tolerability variables 
 
To investigate the safety and tolerability of IN CT001 in pediatric participants in the acute care 
setting experiencing pain of moderate or severe intensity.  

 
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• 
Sedation as assessed by sedation score on the University of Michigan Sedation Scale 
(UMSS) (Malviya et al, Anesthesiology 2004) at the following timepoints: baseline and 10, 
15, 20, 30, 45 and 60 min after first IMP administration. If a second IMP dose is needed, 
sedation will be performed at the timepoints relative to first IMP administration. 
• 
Respiratory depression, assessed by respiratory rate. 
• 
Peripheral Oxygen saturation, as assessed by peripheral oximetry. 
• 
Cardiovascular stability, as assessed by pulse rate. 
• 
Number of reported Adverse Events, graded by intensity and severity.  
• 
Number of AEs reported per participant. 
• 
Local nasal irritation as assessed by combined participant and investigator feedback at 30 
and 60 min post IMP administration. 
 
 Secondary safety and tolerability variables 
To evaluate the feasibility/treatment satisfaction of the nasally administered CT001 for acute pain 
relief in pediatric participants in the emergency setting. 
• 
Treatment satisfaction as assessed by responses to the question: “How satisfied are you 
with the study drug that you/your child received? Please think about how it helped their 
pain, how it was given, any side effects, and how quickly you/your child recovered”. 
Respondents will answer using a 5-point Likert scale (very unsatisfied, unsatisfied, neutral, 
satisfied, very satisfied). 
• 
Feasibility (i.e. acceptance of nasal administration) will be addressed by the healthcare 
staff asking the child: If you were in this situation again and needed pain medication, would 
you like to receive the nasal spray (relative to an injection, tablet or suppository for the 
pain)? If not possible by the child, the parent/legal guardian will assess nasal acceptability. 
Answers will be “yes”, “no”, “I don’t know”. 
• 
Medication errors, defined as any deviation in the IMP administration instructions that result 
in higher or lower dose than planned. Examples may include erroneous priming of the 
pump, too few/many pumps administered, etc. 
 
6.3 
Adverse Events and Serious Adverse Events 
The Investigator should ensure thorough collection of all adverse events (AEs) and concomitant 
medication information associated with each participant. The Investigator should ask the participant 
to report any feeling of being unwell or different from usual in any way during the clinic visit to 
ensure that adverse event (AE) information is recorded in the participant’s source notes and is then 
subsequently entered into the eCRF. Adverse events can be events or symptoms reported by the 
participant. They can also be symptoms and signs observed by study staff.  

 
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All relevant responses from the participant will be recorded in the source notes and eCRF on an 
AE form and graded on severity (mild, moderate, severe), seriousness and relationship to IMP 
(unlikely, possibly, probably). Whenever possible a diagnosis should be given and not just a list of 
signs and symptoms. For further details regarding the classification of AE, please see below. 
All AEs are to be reviewed by the Investigator while ongoing, and subsequently documented at the 
point of resolution. All AEs classified as serious are to be immediately brought to the attention of 
the Investigator by site staff for review and action. All ongoing AEs will be followed up by the 
Investigator until participant discharge or resolution (i.e. AE’s can thus be followed longer than 60 
min post IMP is deemed needed). Additional clinic visits may be scheduled by the Investigator to 
follow-up on AEs according to their clinical judgement. 
 Baseline symptoms 
A baseline symptom is defined as an event that occurs between signing of the assent / ICF until the 
first administration of IMP (i.e. an event that occurs during the screening period). Such events are 
not classified as AEs and will be recorded as baseline symptoms in the Medical History Log in the 
eCRF. 
 Definitions of Adverse Events 
Adverse Event (AE):  
An AE is any untoward medical occurrence in a clinical study participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including clinically 
significant abnormal values from relevant tests, such as clinical safety laboratory tests, ECGs, vital 
signs), symptom, or disease temporally associated with the use of an IMP, regardless of whether 
it is considered related to the IMP. 
A baseline symptom is any medical event in a clinical study subject that occurs after he/she signed 
the ICF up until the first administration of IMP. 
A treatment emergent AE (TEAE) is any AE not present, prior to the initiation of IMP administration 
or any event already present that worsens in either intensity or frequency following exposure to the 
IMP. 
Only TEAEs are collected in this study (i.e., events occurring between screening and the first IMP 
administration are regarded as baseline symptoms and should not be recorded in the AE log in the 
eCRF. 
 
Serious Adverse Events (SAEs): 
An SAE is any AE that: 
• 
results in death 

 
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• 
is life-threatening (this refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death had it been more severe) 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent any of the SAEs defined above) 
Examples of medically important events are intensive treatment in an emergency room for allergic 
bronchospasm or blood dyscrasias, convulsions that do not result in hospitalization, development 
of drug dependency, and drug abuse. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious.  
Non-serious adverse event: 
Is any adverse event that does not meet the definition of an SAE.  
If there is any doubt as to whether an adverse event meets the definition of an SAE, a conservative 
viewpoint must be taken, and the adverse event must be reported as an SAE. 
 
Adverse Reaction:  
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. The phrase "responses to a medicinal product" means that a 
causal relationship between a medicinal product and an AE is at least a reasonable possibility, i.e., 
the relationship cannot be ruled out. For marketed medicinal products, an adverse reaction is a 
response to a drug which is noxious and unintended and which occurs at doses normally used in 
man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function. 
 
Unexpected Adverse Reaction: 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information for the test product (Investigator's Brochure). 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): 
Any serious adverse reaction that might be related to the study medication and are unexpected 
according to the definition above. 

 
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Overdose: 
Is a dose administered to a participant that exceeds the dose prescribed to that participant. Any 
overdose (and associated symptoms) must, at a minimum, be recorded as a non-serious adverse 
event. 
 
6.3.2.1 
Severity 
 
Note that severity is a description of the intensity of the AE and is not to be confused with 
seriousness for which the definitions in 6.3.2 apply. Both seriousness and severity of an AE need 
to be assessed independently. 
 
Mild: 
The adverse event is transient and easily tolerated. 
Moderate: 
The adverse event causes the subject discomfort and interrupts the subject's usual activities. 
Severe: 
The adverse event causes considerable interference with the subject's usual activities and may be 
incapacitating or life-threatening. 
 
6.3.2.2 
Relationship to IMP 
 
The causal relationship between the IMP and the AE should be indicated, using a modified WHO-
UMC causality categories, see Table 3.  
 
Table 3. WHO-UMC Causality Categories 
 
Causality term  
 
Assessment criteria* 
Certain 
 
• 
Event or laboratory test abnormality, with plausible time relationship to 
drug intake 
• 
Cannot be explained by disease or other drugs 
• 
Response to withdrawal plausible (pharmacologically, pathologically) 
• 
Event definitive pharmacologically or phenomenologically (i.e. an 
objective and specific medical disorder or a recognized pharmacological 
phenomenon) 
• 
Rechallenge satisfactory, if necessary 
Probable / 
Likely 
 
• 
Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• 
Unlikely to be attributed to disease or other drugs 
• 
Response to withdrawal clinically reasonable 
• 
Rechallenge not required 
Possible 
 
• 
Event or laboratory test abnormality, with reasonable time relationship to 
drug intake 
• 
Could also be explained by disease or other drugs 

 
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• 
Information on drug withdrawal may be lacking or unclear 
 
Unlikely 
 
• 
Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable (but not impossible) 
• 
Disease or other drugs provide plausible explanations 
 
For data analysis and SAE reporting purposes, AEs classified as ‘unlikely’ will be regarded as ‘not 
related’; AEs classified as ‘possible’, ‘probable/likely’ and ‘certain’ will be regarded as ‘related’. 
 Follow-up of unresolved AEs 
Participants experiencing adverse events will be monitored with appropriate clinical evaluation and 
laboratory tests as indicated by the principal investigator. All subjects with adverse events will be 
followed until satisfactory recovery or stabilization are attained. 
 Reporting of adverse events 
All Adverse Events must be recorded in the case report form, defining relationship to IMP and 
severity. 
As soon as the Investigator is aware of a potential Serious Adverse Event (SAE), he/she should 
contact the local SMERUD monitor by phone, fax or e-mail, and in any case no later than 24 hours 
after the knowledge of such a case.  
If identification of the event occurs outside of office hours, the emergency phone number described 
in the Investigator Site File may be used. At the time of the call, the Investigator must provide as a 
minimum requirement the participant enrolment number, birth date, nature of the SAE, and a 
preliminary assessment of causality. The Investigator should follow up the initial notification of the 
potential SAE by faxing a copy of the SAE reporting form to SMERUD at the number provided in 
the Investigator Site File. The faxed SAE reporting form should be received at SMERUD within 
24 hours after knowledge of such a case. 
Smerud Medical Research International AS  
E-mail: pharmacovigilance@smerud.com  
Fax: +47 23 27 20 01  
Tel: +47 23 27 20 00 
 
Follow-up information on an existing SAE that is fatal or life-threatening should be reported by the 
Investigator to SMERUD within 5 days after the initial report. Where appropriate, hospitalization or 
autopsy reports should be made available. All Serious Adverse Events will be followed up until 
resolution (i.e., asymptomatic, stabilization or death). 

 
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 Reporting of suspected unexpected serious adverse reactions  
Suspected unexpected serious adverse reactions (SUSARs) will be reported by SMERUD 
according to appropriate Competent Authority and Ethics Committee requirements. SMERUD will 
report SUSARs to Investigators on a regular basis according to ICH Good Clinical Practice and to 
local regulations. SUSAR reporting to the Competent Authorities and Ethics Committees will be 
performed according to local regulations in an unblinded manner. The Competent Authorities will 
be notified of all SUSARs through the Eudravigilance database. 
 
Fatal and life-threatening SUSARs should be reported by SMERUD as soon as possible to the 
Competent Authorities and Ethics Committees according to local regulations, and in any case no 
later than seven calendar days, after knowledge by SMERUD of such a case. Relevant follow-up 
information on the case will be subsequently communicated within an additional eight days. All 
other SUSARs shall be reported to the Competent Authorities concerned and to the Ethics 
Committee concerned, according to local regulations, as soon as possible but within a maximum 
of fifteen days of first knowledge by SMERUD. 
 
 
 
 
 
 

 
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7 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT 
 
The principal features of the statistical analyses to be performed are described in this section. A 
more technical and detailed elaboration of the principal features will be presented in a separate 
Statistical Analysis Plan (SAP), which will be signed and approved prior to database lock (DBL). 
7.1 Estimation of Sample Size 
 
So far, data from 375 children on IN sufentanil/ketamine show a safe and tolerable combination 
(data from PDC 01-0201, PDC 01-0203 and PDC 01-0206). Thus, from a safety perspective it is 
expected that 150 patients will be sufficient to capture and confirm the adverse event profile of the 
IMP. Furthermore, a sample size calculation was made for the primary efficacy endpoint on the 
basis of expecting a responder rate of 60%. A previous study reported a responder rate of 71.6 %, 
defined as pain intensity <= 3 at 30 min post IMP (16). With a sample of 113 patients, a one-sample 
one-sided proportion design would provide at least 80% power to show that the responder rate is 
more than to 60%, with a significance level of 5%. Accounting for an approximate 25% dropout rate 
the resulting sample size is 150.  
7.2 
Study Population 
The analysis of data will be based on different subsets according to the purpose of analysis, i.e., 
for efficacy, safety/tolerability, respectively. 
The decision regarding validity of data for each of the analysis sets will be made before DBL. 
 
Enrolled population 
The enrolled population consists of all enrolled participants regardless of receiving study treatment.  
 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all participants who received at least one dose of study 
treatment. The FAS follows the intention-to-treat (ITT) principle, i.e. participants will be analysed, 
regardless of whether treatment was received as planned. The FAS will be used for the analysis of 
primary and secondary objectives. 
7.3 Method of imputation 
The amount of missing data will be reported as appropriate, and no other imputation will be 
performed. 
7.4 Method of statistical analyses 
 

 
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All data will be presented as descriptive analyses only. Continuous variables will be summarised 
using descriptive statistics (number of participants, mean, standard deviation [SD], minimum, 
median, maximum) by age group and as total. Categorical variables will be summarised in 
frequency tables (frequency and proportion) by age group and as total. Graphical presentations will 
be used as appropriate. All changes from baseline endpoints are calculated as the value of the 
corresponding timepoint minus the value at baseline. 
Variables that are based on ordinal scales, such as pain intensity, will be summarized using median 
and interquartile range.  
 
 Analyses addressing the primary objectives 
 
Primary safety and tolerability analysis 
For assessment of safety and tolerability, a multidimensional analysis using descriptive statistical 
methods will be conducted as follows: 
 
Adverse Events 
The number of subjects with adverse events, with possible treatment related adverse events, and 
with serious adverse events (SAE) will be summarised using counts and percentages of subjects 
by age groups. The number and percentage of subjects with adverse events by body system and 
preferred term will be summarised by age group. Adverse event severity and relationship to 
treatment will be summarised by body system, preferred term, and age group. Separate tables may 
be produced for SAEs depending on the number of SAEs occurring in the study. A 95% confidence 
interval will be computed for each percentage/proportion of adverse events. 
 
Respiratory Depression, Peripheral Oxygen Saturation, and Cardiovascular Stability 
These will be assessed by vital signs parameters of respiratory rate, peripheral oximetry, and pulse 
rate respectively. Measured values and changes from baseline will be summarised by mean, 
standard deviation (SD), 95% CI, median, minimum and maximum for each timepoint by age group 
and for all participants. Graphical representation of the measured values and changes from 
baseline in the form of boxplots will be produced for each timepoint (horizontal axis) by each age 
group and for all participants. 
 
Nasal irritation/Tolerability 
 – The number of participants with nasal irritation will be summarised using counts and percentages 
of participant for each timepoint (30 and 60min post IMP administration) by age groups, dose level, 
and type of nasal irritation. A 95% CI of the percentage will be computed and reported. 
 
 

 
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Sedation 
the UMSS scores at assessment timepoints (baseline and 10, 15, 20, 30, 45, and 60 min after IMP 
administration) will be summarised using the median and IQR by age group and dose level. 
Graphical representations of UMSS scores in the form of boxplots will be produced for each 
assessment timepoint (horizontal axis) and for each age group. A 95% confidence interval of the 
mean UMSS score for each time point and by age group if appropriate (i.e., if data is normally 
distributed. 
 
Primary efficacy analysis 
The primary efficacy endpoint will be reported using descriptive statistics only. The analgesic effect 
will be assessed as the proportion of participants that has a reduction of pain intensity to a score 
of 4 or below at 15 min and within 30 minutes post IMP (relative to baseline). A 95% confidence 
interval for the proportion of the participants with a pain reduction of 4 or less within the first 30mins 
post IMP will be evaluated and reported for each age group and for all subjects.  
 
The pain intensity score is measured using different scales for each of the three age groups: 
• 
Numerical Rating Scale, a self-reported ordinal, categorical scale with values 0-10, interval 
1 for subjects aged 9 and less than 18.  
• 
Wong-Baker, a self-reported ordinal, categorical scale with values 0-10, interval 2 for 
subjects aged 5 and less than 9. 
• 
FLACC, an ordinal, categorical scale with values 0-10, interval 1 for subjects aged 1 and 
less than 5. Pain intensity assessment for this age group to be conducted by the 
investigator. 
 
Given that the pain intensity is measured using different scales for each of the three age groups, 
subgroup analyses stratified by measurement scale may be appropriate. Graphical representation 
of pain intensity scores measured within 30mins post IMP administration will be produced in the 
form of boxplots for each age category/assessment scale.  
 
 Analyses addressing the secondary objectives 
 
Secondary safety and tolerability analysis 
 
Treatment Satisfaction 
The general treatment satisfaction score is an ordinal, categorical variable which will be reported 
as median and IQR by age group and for all subjects. 
 
 

 
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Feasibility (Acceptance of Nasal administration) 
The categorical responses ‘Yes’, ‘No’ and ‘I don’t know’ by the child or their caregiver to the 
question: ‘If you were in this situation again and needed pain medication, would you like to receive 
the nasal spray (relative to an injection, tablet or suppository for the pain)?’ will be summarised 
counts and percentages by age group and for all subjects. Frequency graphs may also be used to 
summarise the data.  
 
Medication Errors 
Counts and percentages by age group and dose level will be used to summarise deviations in the 
administration of the IMP that result in higher or lower dosage than planned. 
 
Secondary efficacy analysis 
Need for Supplemental Medication 
The number of children receiving additional analgesics will be summarized using counts, frequency 
tables and graphs by type, dose, and timepoint. 
 
Maximum change in pain intensity within 30 min post IMP administration 
Maximum change in pain intensity within 30 min post IMP administration (relative to baseline) will 
be computed for each subject. The maximum change will be summarised by the median and IQR 
by age group and dose level. Average time from IMP to maximum change in pain intensity will also 
be reported. 
 
30% (or more) reduction in pain intensity within 30 min post IMP administartion 
The number of subjects that achieve at least 30% reduction in pain intensity relative to baseline 
within 30 min post IMP administration will be summarized using counts and percentages (frequency 
tables) and reported by type, dose level, and timepoint. 
 
Change in pain intensity 
The change in pain intensity from baseline will be computed for each subject at 10, 15, 20, 30, 45 
and 60 min post IMP and this parameter will be summarized by the median and IQR and reported 
by age group and dose level. 
 
7.5 Data Collection / Case Report Forms  
Data will be collected using an electronic data capture (EDC) solution. Electronic Case report forms 
(eCRFs) will be utilised for recording data from each subject meeting the eligibility criteria and being 

 
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included in the study. The eCRF system, ViedocTM, will be available on an internet portal accessible 
through any standard computer device with internet access. All study staff responsible for entering 
data into the eCRF system will be trained at the Investigator meeting and/or by the Clinical 
Research Associate (CRA) prior to the start-up of the study. A personal log-in will be provided for 
all responsible personnel to allow for an audit trail relating to the study data to be maintained. No 
clinical trial information will be transferred via the eCRF system until the site has been qualified 
through completion of a validation eCRF.  
 
All evaluations performed shall be entered in a timely manner into the eCRF by a member of the 
site staff delegated responsibility for this specific task by the Principal Investigator (PI) of the clinical 
site. It is the responsibility of the Investigator to ensure that the eCRFs are properly completed. The 
data in the eCRFs should be consistent with the relevant source documents.  The Investigator will 
sign the designated signature fields of the eCRF data entry screens to confirm that the information 
on each screen is accurate and complete. All data must be stored in an unidentifiable form treated 
with strict confidentiality in accordance with applicable data protection regulations. 
 
Captured data will be monitored electronically and Source Data Verification (SDV) will take place 
at the site, i.e. relevant information (as outlined in the monitoring plan) will be verified against the 
individual subject records unless the eCRF is considered source data.  
 
Any inconsistencies will be presented as queries; either as automatically generated queries if raised 
by the logical data checks of the eCRF system, or by manually generated queries if raised by the 
data validation checks or the SDV performed by the Data Manager (DM) or the CRA respectively. 
Queries shall be resolved in a timely member by a trained member of the site staff.  
7.6 Data Management 
Data will be transmitted electronically into the web-based EDC system. Upon receipt, data will be 
coded according to pre-specified dictionaries and in accordance with the CROs Standard Operating 
Procedures (SOP). The handling of data, including data quality control, will comply with all 
applicable regulatory guidelines. 
 
8 
REGULATORY AND ADMINISTRATIVE PROCEDURES 
8.1 Institutional Review  
The procedures set out in this study protocol are designed to ensure that the Sponsor, the CRO 
and Investigator abide by the principles of the Guideline for Good Clinical Practice (GCP) of the 
International Conference of Harmonization (ICH) Good Clinical Practice as last amended in 2016, 
in the conduct, evaluation and documentation of this study (17). Further, the study will be conducted 

 
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in accordance with the moral, ethical and scientific principles governing clinical research as set out 
in the World Medical Association. WMA Declaration of Helsinki – Ethical Principles for Medical 
Research Involving Human Subjects. World Medical Association 1964, Amended 2013. The study 
will further be carried out in accordance with any additional local legal requirements. 
 
The Protocol and the Subject Information Sheet / Informed Consent Form / Assent Form will be 
approved by the relevant Competent Authorities and Ethics Committees, and possibly other public 
bodies according to local requirements before commencement. If a protocol amendment is 
necessary, this will be prepared with the agreement of the Principal Investigator and signed by the 
relevant parties. If the amendment is considered substantial, it will be submitted to the Competent 
Authorities and Ethics Committees, and possibly other public bodies according to local 
requirements for review and approval. The protocol amendment will not be implemented before the 
required approvals are obtained. Minor amendments which do not affect the safety or physical or 
mental integrity of the clinical trial subjects or the scientific value of the trial (i.e. non-substantial 
amendments) will not be submitted to Competent Authorities or Ethics Committees.  
 
SUSAR reports and Periodic Safety Reports will be sent to Competent Authorities and Ethics 
Committees according to local regulations.   
 
8.2 Subject Information / Informed Consent  
 
In the following, the word study subject includes the participant and/or the accompanying 
parent/legal guardian. 
The Investigator is responsible for giving the study subject full and adequate verbal and written 
information about the nature, purpose, possible risk, and benefit of the study. Information about the 
study and obtaining consent may be delegated to an experienced study nurse. Study subjects must 
also be notified that they are free to withdraw from the study at any time. The subjects should have 
reasonable time to read and understand the information before signing. The Investigator is 
responsible for obtaining signed informed consent from all subjects before including the subject in 
any study related procedures. A copy of the participant information and of the signed Informed 
Consent Form / Assent Form in local language, will be given to the subjects. One original copy of 
the signed Informed Consent form / Assent Form will be kept by the subject and one copy will be 
retained at the study site. 

 
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8.3 Subject Confidentiality and Data Protection 
 Subject confidentiality 
The Investigator must ensure that subject’s confidentiality will be maintained. eCRFs or other 
documents submitted to the sponsor should only identify subjects by their initials and study number. 
The Investigator should keep a separate log of subject codes and names. Documents not for 
submission to the Sponsor, e.g., subject’s completed Consent Forms, should be retained by the 
Investigator in strict confidence. 
 
The Investigator is required to record primary efficacy and safety data, concomitant medication, 
and subject progress in the subject’s file/notes/medical record. 
 
The subject’s medical records (source data) will be reviewed by the study monitor and possibly by 
other sponsor personnel or regulatory authorities, to verify adequate source documentation, 
accuracy, and completeness of eCRFs. The review will be conducted with strict adherence to 
professional standards of confidentiality. No participant identifiable data will be taken out of the 
investigator site. 
 
All subjects screened for the study will have their initials and birth date entered chronologically on 
the Subject Screening Log at the initial visit. An explanation for exclusion from admission to the 
protocol is to be provided on the Subject Screening Log. 
 Data Protection 
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to investigate the potential effects of the study drug. Collection, 
handling, and storage of personal data from the clinical trial will only take place as described in the 
PIS/ICF as well as in section 7.5 (Data Collection) and in accordance with the General Data 
Protection Regulation (EU 2016/679), current EU Clinical Trial Regulations (regulation 536/2014) 
and any applicable local regulations. 
 
A dedicated Data Protection Officer (DPO) employed by SMERUD is registered at the Data 
Protection Authority. The DPO will always supervise that the subjects’ data protection is maintained 
by auditing and approving the electronic data capture (EDC) provider, ensuring data protection 
procedures are in place and ensuring that the annual audit programs include also checks of subject 
data protection. 
8.4 Subject Treatment Plan 
The subjects are otherwise generally healthy children attending the ED for different indications.  

 
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8.5 GCP 
The procedures set out in this study protocol are designed to ensure that the Sponsor, the CRO 
and Investigator abide by the principles of the Guideline for Good Clinical Practice (GCP) of the 
International Conference of Harmonization (ICH) Good Clinical Practice as last amended in 2016, 
in the conduct, evaluation and documentation of this study. 
8.6 Essential Documents 
The ICH guideline for GCP lists several essential GCP documents required prior to, during and 
after the conduct of the study. It is the responsibility of the monitor to ensure that the Investigator 
is always provided with a copy of such documents prepared by the study management, and it is 
likewise the responsibility of the Investigator to provide the monitor with essential documents 
prepared by the Investigator or the local Ethics Committee.  
 
Record Retention 
The investigator site file, eCRFs and all medical records upon which the eCRFs are based (source 
data) must be kept for at least 25 years or according to local legislation whichever is the longest 
after completion of the study. Image carriers or other data carriers may be used for this purpose. 
The documentation should be easily retrievable and readable during the entire archiving duration. 
8.7 Monitoring / Quality Control 
Prior to the start of the study, the Study monitor will review the protocol and eCRFs with the 
Investigator and his/her staff. The Investigator will be visited on a regular basis by the study monitor, 
who will check study procedures, including safety assessments, IMP handling, data recording and 
perform source data verification (SDV). The study monitor must be allowed to review subject 
records to confirm that required protocol procedures are being followed and check consistency 
between subject record and eCRF data. Incorrect or missing entries in the ECRFs will be queried 
and must be corrected in a timely manner.  
8.8 Quality Assurance  
During or after the study is completed, sponsor representatives or regulatory authorities may wish 
to carry out an audit or an inspection. These representatives must have the same access to study 
data and subject source data as the study monitor. 
8.9 Insurance and Liability 
Participants taking part in this clinical study are insured by the Sponsor against any injury caused 
by the clinical study, in accordance with the local regulatory requirements. A copy of the insurance 
certificate will be provided to each investigator and will be filed in the investigator’s file at the sites 

 
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and in the clinical trial’s Trial Master File (TMF). The investigator must notify the Sponsor 
immediately upon notice of any claims or lawsuits brought by the participants or their relatives. 
8.10 End of Trial 
Regular Trial Termination 
The end of the trial is defined as the last visit of the last subject included in the trial. Within 90 days 
of the end of the trial, the Sponsor/CRO will notify the Competent Authority and the Ethics 
Committee of the regular termination of the study as required according to national law and 
regulations.  
Premature Trial Termination  
For safety reasons, this trial may be terminated prematurely at any time by the sponsor, the 
Principal investigator or competent authorities. If the sponsor decides to terminate the trial for any 
reason, including or administrative reasons, the investigator, ethics committee and competent 
authority will be informed about the reason(s) for stopping the study. 
8.11 Study Report 
A clinical study report (CSR) will be prepared covering clinical and statistical aspects and 
summarising all findings of the clinical study. The content must be treated as strictly confidential. 
The study report will be sent to the Investigators, the Competent Authorities and Ethics Committees 
according to local requirements. 
8.12 Publication and Data Rights 
Study results, positive as well as inconclusive will be made publicly available at 
www.clinicaltrials.gov and www.clinicaltrialsregister.eu.  
The Sponsor recognizes the traditional freedom of scientists to publish and present promptly the 
results of their studies and the Sponsor is committed to present or publish the results of this study, 
both if the results are positive, negative, or inconclusive. The presented or published data should 
be done using clean, checked, and validated data only, to ensure the accuracy of the results. 
The Investigator shall provide any and all disclosures (including, without limitation, manuscripts, 
abstracts, poster presentations, any public disclosure by lecture, seminar, thesis, patent application 
or other means) to the Sponsor for reviewing and commenting at least sixty (60) days before 
planned publication. All proposed disclosures shall be in final form such that the Sponsor can review 
the proposed disclosure in completion and in context. Any information identified by the Sponsor as 
confidential must be deleted prior to submission. 
The Sponsor may require any proposed disclosure to be delayed for up to 3 months to enable a 
patent application to be prepared and filed. 

 
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Published research material shall acknowledge the assistance and contribution of the involved 
parties in accordance with standard academic practices, including acknowledgement via co-
authorship where appropriate. 
 
 
 

 
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9 
REFERENCES 
1. 
EMA 001739-PIP02-16. Available from: https://www.ema.europa.eu/en/documents/pip-
decision/p/0413/2019-ema-decision-6-december-2019-agreement-paediatric-investigation-
plan-granting-waiver-sufentanil/ketamine-hydrochloride-emea-001739-pip02-16_en.pdf 
2. 
Weber F, Wulf H, el Saeidi G. Premedication with nasal s-ketamine and midazolam provides 
good conditions for induction of anesthesia in preschool children. Can J Anaesth J Can Anesth. 
2003 May;50(5):470–5.  
3. 
Roelofse JA, Shipton EA, de la Harpe CJ, Blignaut RJ. Intranasal sufentanil/midazolam versus 
ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing 
multiple dental extractions under general anesthesia: a prospective, double-blind, randomized 
comparison. Anesth Prog. 2004;51(4):114–21.  
4. 
Summary of product characteristics, Sufenta, solution for injection. Danish Health and 
Medicines 
Authority; 
2020 
March 
6 
[Internet]. 
Available 
from: 
https://view.officeapps.live.com/op/view.aspx?src=http%3A%2F%2Fspcweb.dkma.dk%2FSP
CREPL%2FHuman%2FS%2FSufenta%2C%2520injektionsv%25c3%25a6ske%2C%2520opl
%25c3%25b8sning%25205%2520mikg-ml%2C%252050%2520mikg-
ml.doc&wdOrigin=BROWSELINK 
5. 
Summary of product characteristics, Ketamin Abcur, solution for injection. Danish Health and 
Medicines 
Authority; 
2020 
Jun 
18. 
[Internet]. 
Available 
from: 
https://view.officeapps.live.com/op/view.aspx?src=http%3A%2F%2Fspcweb.dkma.dk%2FSP
CREPL%2FHuman%2FK%2FKetamin%2520Abcur%2C%2520injektionsv%25c3%25a6ske
%2C%2520opl%25c3%25b8sning%252010%2520mg-ml%2520og%252050%2520mg-
ml.docx&wdOrigin=BROWSELINK 
6. 
Dahmani S, Michelet D, Abback PS, Wood C, Brasher C, Nivoche Y, et al. Ketamine for 
perioperative pain management in children: a meta-analysis of published studies. Paediatr 
Anaesth. 2011 Jun;21(6):636–52.  
7. 
Summary of product characteristics S-ketamine ‘Pfizer’ solution for injection 2020 October 28 
[Internet]. Available from: https://labeling.pfizer.com/ShowLabeling.aspx?id=3929 
8. 
https://www.karolinska.se/globalassets/global/4-gamla-kataloger/tema-barn-och-
kvinnosjukvard/barn-perioperativ-medicin-och-intensivvard/riktlinjer-smarta-barn.pdf 
[Internet]. 
Available 
from: 
https://www.karolinska.se/globalassets/global/4-gamla-
kataloger/tema-barn-och-kvinnosjukvard/barn-perioperativ-medicin-och-intensivvard/riktlinjer-
smarta-barn.pdf 
9. 
Lundeberg S, Roelofse JA. Aspects of pharmacokinetics and pharmacodynamics of sufentanil 
in pediatric practice. Paediatr Anaesth. 2011 Mar;21(3):274–9.  
10. Nielsen BN, Friis SM, Rømsing J, Schmiegelow K, Anderson BJ, Ferreirós N, et al. Intranasal 
sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014 Feb;24(2):170–80.  
11. Yaster M, Benzon HT, Anderson TA. “Houston, We Have a Problem!”: The Role of the 
Anesthesiologist in the Current Opioid Epidemic. Anesth Analg. 2017 Nov;125(5):1429–31.  
12. Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, et al. New Persistent 
Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surg. 2017 Jun 
21;152(6):e170504.  

 
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13. Krane EJ, Weisman SJ, Walco GA. The National Opioid Epidemic and the Risk of Outpatient 
Opioids in Children. Pediatrics. 2018 Aug;142(2):e20181623.  
14. Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs. 
1988;14(1):9–17.  
15. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for 
scoring postoperative pain in young children. Pediatr Nurs. 1997;23(3):293–7.  
16. Blancher M, Maignan M, Clapé C, Quesada JL, Collomb-Muret R, Albasini F, et al. Intranasal 
sufentanil versus intravenous morphine for acute severe trauma pain: A double-blind 
randomized non-inferiority study. Matchett G, editor. PLOS Med. 2019 Jul 16;16(7):e1002849.  
17. ICH Harmonised Guideline: Integrated addendum to ICH E6 (R1), Guideline for Good Clinical 
Practice 
E6(R2) 
Current 
Step5 
14 
June 
2017. 
Available 
from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-
clinical-practice-step-5_en.pdf 
 

 
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10 
SUMMARY OF PROTOCOL AMENDMENTS 
 
 
Protocol version 
Includes 
amendment no.  
Main changes 
 
1.0 
 
Not applicable 
 
Not applicable 
2.0 
 
01 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
- 
 
3.0 
2.0 
 
 
 
 
 
 
 
 
 
3.1 
Non 
substantial 
changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2 
Non 
substantial 
changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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11 
SIGNATURES 
 
The protocol has been approved by:  
 
 
Name and function 
Signature 
Date 
 
 
 
Senior Medical Monitor 
 
 
 
 
 
 
Head of Clinical 
Development and Operations 
 
 
 
 
 
 
 
Coordinating Investigator 
 
 
 
 
 
 

 
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12 
SIGNATURE PAGE FOR INVESTIGATOR 
 
By signing this page, the Investigator confirms having read the entire protocol and its appendices 
and agrees to conduct this study in accordance with the protocol, GCP, the Declaration of 
Helsinki, Clinical Trials Regulation EU No 536/2014 and national regulations.  
 
The signature also confirms that the Investigator agrees that the results of this study may be used 
for submission to national and/or international registration and supervising authorities. The 
authorities will be notified of the Investigators name, address, qualifications and extent of 
involvement. 
 
Name 
Signature 
Date 
 
 
 
 
 
 
 
 
 

 
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13 
APPENDICES 
 
A. Numerical Rating scale for pain intensity ratings 
B. Wong-Baker Faces scale 
C. FLACC scale 
D. Sedation scoring – university of Michigan Sedation Score 
E. Treatment satisfaction 

 
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Appendix A 
 
 
 
 

 
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Appendix B 
 
 
 
 
 
 
Wong-Baker scale for self-rating of pain in verbal children ≥ 5 up to 9 
years old. 
 
 
 
 
 

 
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Appendix C 
 
 
 
 
 
 

 
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Appendix D 
 
 
 
 
Michigan University Sedation Scale 
 
 
 
S. Malviya* , T. Voepel-Lewis, A. R. Tait, S. Merkel, K. Tremper and N. Naughton. Depth of sedation 
in children undergoing computed tomography: validity and reliability of the University of Michigan 
Sedation Scale (UMSS) British Journal of Anaesthesia 88 (2): 241±5 (2002) 
 
 
 

 
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Appendix E 
 
 
 
 
 
Treatment Satisfaction 
 
Patient no:_____    Date:_________    Time:_________ 
 
 
How satisfied are you with the study drug that you/your child received? Please 
think about how it helped their pain, how it was given, any side effects, and how 
quickly you/your child recovered.