Overview
Sponsor-declared trial summary
Phase
Therapeutic confirmatory (Phase III)
Status
Ongoing, recruiting
Participants planned
447
Countries
1
Sites
1
Acute traumatic pain
Determine whether intranasal (IN) fentanyl, intravenous (IV) esketamine and intranasal esketamine are non-inferior to intravenous fentanyl for analgesia in acute traumatic pain in the prehospital environment
Key facts
- Sponsor
- Amsterdam UMC
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Not possible to specify
- Trial duration
- 20 May 2025 → ongoing
- Decision date (initial)
- 2023-08-29
- Transition trial
- No
- Low-intervention
- Yes
- Rare-disease indication
- No
- Vulnerable population
- No
- Funding sources
- Stichting Ziektekosten Verzekering Krijgsmacht
External identifiers
- EU CT number
- 2022-500176-63-00
- WHO UTN
- U1111-1287-7486
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy, Efficacy, Safety
Determine whether intranasal (IN) fentanyl, intravenous (IV) esketamine and intranasal esketamine are non-inferior to intravenous fentanyl for analgesia in acute traumatic pain in the prehospital environment
Secondary objectives 2
- Determine whether - compared to fentanyl IV - fentanyl IN, esketamine IV and esketamine IN provide similar patient satisfaction considering analgesia
- To determine whether - compared to fentanyl IV - fentanyl IN, esketamine IV and esketamine IN are equally safe
Conditions and MedDRA coding
Acute traumatic pain
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 4
- Age ≥18 years
- Pain caused by trauma that occurred on the same day
- Administration of a strong opioid or esketamine is required for analgesia as determined by prehospital personnel
- Patient will be transported to a hospital
Exclusion criteria 8
- Reported or estimated weight <40 or >100 kg
- Subject does not understand Dutch or English
- Subject is known to have previously declined participation in medical research
- Inability to report pain score
- Inability to give intranasal or intravenous medication
- Known severe cardiovascular disease
- Pre-eclampsia
- Glasgow Coma Scale score < 11
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Difference in NRS score between baseline and 10 minutes after administration of study medication
Secondary endpoints 9
- Difference in NRS score between baseline and 20 minutes after first dose of study medication
- Difference in NRS score between baseline and arrival at the hospital
- Relative change in NRS score between baseline and 10 minutes after first dose of study medication
- Relative change in NRS score between baseline and 20 minutes after first dose of study medication
- Relative change in NRS score between baseline and arrival at the hospital
- Number of subjects requiring a second dose of study medication
- Number of subjects requiring unblinding because of treatment failure
- Number of subjects experiencing adverse events, need for unblinding or intervention
- Patient satisfaction with prehospital analgesia
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 4
Esketiv 25 mg/ml, oplossing voor injectie
PRD7033666 · Product
- Active substance
- Esketamine
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 0.4 mg/kg milligram(s)/kilogram
- Max total dose
- 0.4 mg/kg milligram(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- N01AX14 — ESKETAMINE
- Marketing authorisation
- RVG 121114
- MA holder
- EUROCEPT INTERNATIONAL BV
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB25825 · Substance
- Active substance
- Esketamine
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRANASAL USE
- Max daily dose
- 0.8 mg/kg milligram(s)/kilogram
- Max total dose
- 0.8 mg/kg milligram(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB02129MIG · Substance
- Active substance
- Fentanyl Citrate
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRANASAL USE
- Max daily dose
- 2.0 µg/Kg microgram(s)/kilogram
- Max total dose
- 2.0 µg/Kg microgram(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Fentanyl hameln 50 microgram/ml, oplossing voor injectie
PRD3238668 · Product
- Active substance
- Fentanyl Citrate
- Substance synonyms
- FENTANYL DIHYDROGEN CITRATE, 2-HYDROXYPROPANE-1,2,3-TRICARBOXYLIC ACID, N-(1-PHENETHYL-4-PIPERIDYL)-N-PHENYL-PROPANAMIDE
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 2.0 µg/Kg microgram(s)/kilogram
- Max total dose
- 2.0 µg/Kg microgram(s)/kilogram
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- N01AH01 — FENTANYL
- Marketing authorisation
- RVG 25458
- MA holder
- HAMELN PHARMA GMBH
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Placebo 2
Natriumchloride 0,9% oplossing voor injectie
PRD2503472 · Product
- Active substance
- Sodium Chloride
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 20 ml millilitre(s)
- Max total dose
- 20 ml millilitre(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- B05XA03 — SODIUM CHLORIDE
- Marketing authorisation
- RVG 57789
- MA holder
- FRESENIUS KABI NEDERLAND B.V.
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SUB12581MIG · Substance
- Active substance
- Sodium Chloride
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INTRANASAL USE
- Max daily dose
- 4 ml millilitre(s)
- Max total dose
- 4 ml millilitre(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Auxiliary 5
Midazolam Aurobindo 5 mg/ml, oplossing voor injectie/infusie of rectale toediening
PRD6716864 · Product
- Active substance
- Midazolam Hydrochloride
- Pharmaceutical form
- SOLUTION FOR INJECTION/INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 1 mg milligram(s)
- Max total dose
- 1 mg milligram(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- N05CD08 — MIDAZOLAM
- Marketing authorisation
- RVG 22596
- MA holder
- AUROBINDO PHARMA B.V.
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Paracetamol B. Braun 10 mg/ml, oplossing voor infusie
PRD607807 · Product
- Active substance
- Paracetamol
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS USE
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 1000 mg milligram(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- N02BE01 — PARACETAMOL
- Marketing authorisation
- RVG 109193
- MA holder
- B.BRAUN MELSUNGEN AG
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Paracetamol Sanias 500 mg, tabletten
PRD5589786 · Product
- Active substance
- Paracetamol
- Substance synonyms
- ACETAMINOPHEN
- Pharmaceutical form
- TABLET
- Route of administration
- ORAL
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 1000 mg milligram(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- N02BE01 — PARACETAMOL
- Marketing authorisation
- RVG 119201
- MA holder
- AUROBINDO PHARMA B.V.
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Diclofenacnatrium Aurobindo 50 mg, maagsapresistente tabletten.
PRD1780602 · Product
- Active substance
- Diclofenac Sodium
- Substance synonyms
- DICLOFENACUM NATRICUM, DICLOPHENAC SODIUM, SODIUM 2-[2-[(2,6-DICHLOROPHENYL)AMINO]PHENYL]ACETATE
- Pharmaceutical form
- GASTRO-RESISTANT TABLET
- Route of administration
- ORAL
- Max daily dose
- 50 mg milligram(s)
- Max total dose
- 50 mg milligram(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- M01AB05 — DICLOFENAC
- Marketing authorisation
- RVG 16274
- MA holder
- AUROBINDO PHARMA B.V.
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Diclofenac Na CF 25 mg/ml, oplossing voor injectie
PRD515578 · Product
- Active substance
- Diclofenac Sodium
- Substance synonyms
- DICLOFENACUM NATRICUM, DICLOPHENAC SODIUM, SODIUM 2-[2-[(2,6-DICHLOROPHENYL)AMINO]PHENYL]ACETATE
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INTRAMUSCULAR
- Max daily dose
- 75 mg milligram(s)
- Max total dose
- 75 mg milligram(s)
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- M01AB05 — DICLOFENAC
- Marketing authorisation
- RVG 17256
- MA holder
- CENTRAFARM B.V.
- MA country
- Netherlands
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Amsterdam UMC
- Sponsor organisation
- Amsterdam UMC
- Address
- P. O. Box 7057
- City
- Amsterdam
- Postcode
- 1007 MB
- Country
- Netherlands
Scientific contact point
- Organisation
- Amsterdam UMC
- Contact name
- R.P. Weenink
Public contact point
- Organisation
- Amsterdam UMC
- Contact name
- R.P. Weenink
Locations
1 EU/EEA country · 1 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Netherlands | Ongoing, recruiting | 447 | 1 |
| Rest of world | — | 0 | — |
Investigational sites
Ambulance Amsterdam
Medical Manager, Karperweg 19-25, 1070BS, Amsterdam
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Netherlands | 2024-01-11 | 2024-01-11 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 3 · Art. 52 CTR
Serious breach SB-32072
- Sponsor became aware
- 2024-06-27
- Date of breach
- 2024-06-14
- Submission date
- 2024-07-01
- Member states concerned
- Netherlands
- Categories
- Protocol
- Areas impacted
- Data reliability or robustness
- Benefit-risk balance changed
- No
- Description
- Subject was included while not meeting inclusion criterium "age ≥18 years". The research nurse was under the impression the subject was ≥18 years old. However, the subject turned out to be 16 years old.
Impact on subject rights: there is no impact on the subjects rights, since subjects do not need to be informed or asked for consent before start of the study (deferred consent).
Impact on subject safety: there is no impact on subject safety because we are performing a low-intervention trial where all study arms are standard of care. If the subject was not included in the trial, he/she would still have received either fentanyl and/or esketamine for pain treatment.
Impact on reliability and robustness of the study data: there is an impact on reliability and robustness of the study data, since the subject does not belong to our study population. However, since our primary analysis includes both an intention-to-treat and per protocol analysis, this will be corrected for. - Sponsor actions
- The occurrence has been discussed with the according research nurse.
The importance of the age check will be stressed to the investigators of the clinical trials site. If the subject is not able to verify his/her age, subjects will not be included in the study.
The investigator will also inform the subject of this occurrence.
The sponsor would like to mention that in prehospital care, complete background information might not be available at the first moment the care provider approaches the patient. Combined with the emergency setting of this trial, this might have contributed to this occurrence. Nonetheless, this mistake should have been prevented by thorough screening of the subject by the research nurse.
| Organisation | City | Country | Type |
|---|---|---|---|
| Ambulance Amsterdam | Amsterdam | Netherlands | Other |
Serious breach SB-21750
- Sponsor became aware
- 2024-04-17
- Date of breach
- 2024-04-13
- Submission date
- 2024-04-23
- Member states concerned
- Netherlands
- Categories
- Protocol
- Areas impacted
- Subject safety
- Benefit-risk balance changed
- Yes
- Description
- According to protocol, subjects should always receive study medication through both routes of administration (IV and IN). The analgesic (either fentanyl or esketamine) is administered through one route, while the placebo is administered through the other. The research nurse is not aware through what route the analgesic is administered.
On this occasion, the subject only received IV study medication. This means the subject potentially received only placebo (since it is not known through what route the analgesic is administered). After 20 minutes the subject was unblinded because (s)he required additional analgesia (this is according to protocol).
Conclusion: this protocol breach has potentially led to the subject experiencing sustained pain. - Sponsor actions
- This issue has been discussed with the according research nurse. At the next team meeting, there will be a concise update on the study and issues to be addressed.
| Organisation | City | Country | Type |
|---|---|---|---|
| Ambulance Amsterdam | Amsterdam | Netherlands | Other |
Serious breach SB-49113
- Sponsor became aware
- 2024-09-30
- Date of breach
- 2024-08-08
- Submission date
- 2024-10-01
- Member states concerned
- Netherlands
- Categories
- Protocol
- Areas impacted
- Subject safety
- Benefit-risk balance changed
- Yes
- Description
- According to protocol, a subject should be unblinded if he/she requires more pain relief after receiving two doses of study medication. The subject then continues to receive regular medical care and additional analgesia is given at the discretion of prehospital personnel. This procedure has been installed to minimalize the risk of subjects experiencing sustained moderate to severe pain. It also enables prehospital personnel to decide what additional analgesia is appropriate. For example, prehospital personnel might decide to administer the alternative analgesic (e.g. administering fentanyl when two doses of esketamine have been given). This reflects standard care where, if a patient does not respond to a single analgesic, administration of an additional alternative analgesic is common.
On this occasion, instead of unblinding the subject, prehospital personnel administered a third dose of study medication (similar to the second dose). This impacts subject safety as the unblinding procedure is installed to minimalize the risk of subjects experiencing sustained pain.
Just for clarification: the study kit includes a limited quantity of study medication (2 doses of study medication for a maximum weight of 100kg). However, due to this subject being lightweight, there was enough study medication remaining to administer a third dose (similar to the second dose). - Sponsor actions
- The occurrence has been discussed with the according research nurse.
The study team is planning a new round of training sessions for all research nurses and research assistants to update / refresh their knowledge about the trial. This includes discussing all serious breaches and important deviations. The training sessions will start in october.
| Organisation | City | Country | Type |
|---|---|---|---|
| Ambulance Amsterdam | Amsterdam | Netherlands | Other |
Temporary halts 1 · Art. 38 CTR
Temporary halt TH-70074
- Halt date
- 2025-02-10
- Member states concerned
- Netherlands
- Publication date
- 2025-02-10
- Reason
- Safety related (clinical or pre-clinical results)
- Explanation
- All documentation concerning this issue will be presented to the IRB in a substantial amendment. Pending IRB review, the trial will not enroll any subjects.
- Follow-up measures
- Substantial amendment will be submitted to the IRB. No follow-up measures for subjects are required.
- Benefit-risk balance changed
- Yes
- Treatment stopped
- No
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 8 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2022-500176-63-00 (clean) | 3 |
| Protocol (for publication) | D1_Protocol 2022-500176-63-00 not for publication (track changes) | 9 |
| Protocol (for publication) | D1_Protocol 2022-500176-63-00_redacted | 9 |
| Recruitment arrangements (for publication) | K1_Recruitment arrangements | 2 |
| Subject information and informed consent form (for publication) | L1_objection letter NL clean | 2 |
| Subject information and informed consent form (for publication) | L1_objection letter NL track changes | 2 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF adults (clean) | 3 |
| Subject information and informed consent form (for publication) | L2_Other subject information material information leaflet adults (clean) | 3 |
Application history
5 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2023-05-17 | Netherlands | Acceptable 2023-08-29
|
2023-08-29 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2024-05-13 | Netherlands | Acceptable 2024-06-19
|
2024-06-19 |
| 3 | SUBSTANTIAL MODIFICATION | SM-2 | 2025-02-13 | Netherlands | Acceptable 2025-05-12
|
2025-05-12 |
| 4 | SUBSTANTIAL MODIFICATION | SM-3 | 2025-05-19 | Netherlands | Acceptable 2025-05-19
|
2025-05-19 |
| 5 | SUBSTANTIAL MODIFICATION | SM-4 | 2025-07-17 | Netherlands | Acceptable 2025-08-28
|
2025-08-29 |