Opioid-Free Analgesia In Intensive Care Unit (OFICU)

Start 24 Nov 2025 · Status Ongoing, recruitment ended · 1 EU/EEA countries · 1 sites · Protocol LOCAL/2022/RW-01

Overview

Sponsor-declared trial summary

Phase Therapeutic use (Phase IV)

Status Ongoing, recruitment ended

Participants planned 50

Countries 1

Sites 1

Intubation

Compare daily remifentanil consumption, between the 24th hour and the 48th hour after randomization of ICU patients requiring at least 72 hours of mechanical ventilation, between patients following a standardized multimodal analgesia strategy without major opioids and patients following the conventional strategy

Key facts

Sponsor: Centre Hospitalier Universitaire De Nimes
Participant type: Patients
Age range: 18-64 years, 65+ years
Gender: Male and Female
Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
Trial duration: 24 Nov 2025 → ongoing
Decision date (initial): 2024-10-17
Transition trial: Yes
Low-intervention: No
Rare-disease indication: No
Vulnerable population: Yes
Funding sources: CHU de Nimes

External identifiers

EU CT number: 2024-517770-14-00
EudraCT number: 2022-003273-37
ClinicalTrials.gov: NCT05825560

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

Secondary objectives 13

Impact of a non-opioid analgesia strategy on morphine savings at D7
Impact of an opioid-free analgesia strategy on morphine exposure time
Impact of an opioid-free analgesia strategy on sedative consumption
Impact of a non-opioid analgesia strategy on the duration of mechanical ventilation
Impact of a non-opioid analgesia strategy on organ failure at D28
Impact of a non-opioid analgesia strategy on fluid intake
Impact of a non-opioid analgesia strategy on mental confusion
Impact of a non-opioid analgesia strategy on the occurrence of morphine-related adverse events
Impact of a non-opioid analgesia strategy on the incidence of ventilator-associated pneumonia
Impact of a non-opioid analgesia strategy on extubation failure rates
Impact of a non-opioid analgesia strategy onICU and hospital length of stay
Impact of the non-opioid analgesia strategy on vital prognosis at D28 and D90
Impact of a non-opioid analgesia strategy on morphine dependence at D90

Conditions and MedDRA coding

Intubation

Version	Level	Code	Term	System organ class
21.1	PT	10022519	Intensive care	100000004865

Study design 1 period

#	Title	Allocation	Blinding	Roles blinded	Arms
1	standardized multimodal analgesia strategy without major opioids vs conventional strategy comparison of daily remifentanil consumption, between the 24th hour and the 48th hour after randomization of patients admitted to the ICU and requiring at least 72 hours of mechanical ventilation, between patients following a standardized multimodal analgesia strategy without major opioids and patients following the conventional strategy	Randomised Controlled	Double	[{"id":145749,"code":1,"name":"Subject"},{"id":145751,"code":5,"name":"Carer"},{"id":145747,"code":3,"name":"Monitor"},{"id":145750,"code":2,"name":"Investigator"},{"id":145748,"code":4,"name":"Analyst"}]	Interventional stategy opioid free: A fixed combination of nefopam and tramadol will be initiated at daily doses of 400mg and 120mg respectively. For pharmacodynamic reasons, an initial dose of 50mg tramadol and 20mg nefopam IVL over 30 minutes will be administered. Analgesia is re-evaluated every 30 minutes for the first two hours (and after each analgesic adjustment), then every 2 hours. Conventional stategy: Analgesia is provided by a combination of paracetamol and remifentanil, adapted according to a tiered administration system based on BPS and theoretical ideal weight. Remifentanil doses are adjusted in stages to ensure that the patient has a BPS score of 4 or less. Analgesia is reassessed every 30 minutes until analgesic adaptation is complete, and then every 2 hours.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

Patient hospitalized in ICU and requiring sedation-analgesia for mechanical ventilation
Patient undergoing mechanical ventilation for more than 2 hours and less than 24 hours.
Informed consent signed by the patient or his trusted person, legal representative, family member, curator or tutor, or emergency consent procedure
Patient affiliated to the French Government Public Health Insurance
Patient over 18 years old

Exclusion criteria 9

Patient already involved in a trial that might influence our primary endpoint
Patient in exclusion-period determined by another trial or study
Patient who is likely to be requiring less than 48 hours of mechanical ventilation
Patient with contraindication or allergies to at least one of the following medication : paracetamol, nefopam, tramadol, ketamine, remifentanil
Patient with hepatic insufficiency (defined as PT < 50%)
Parturient or breast-feeding patient
Patient suffering from moderate to severe Acute Respiratory Distress Syndrome (ARDS), with decreased PaO2/FiO2 ratio under 150mmHg after respiratory optimization (courant volume 6mL/kg and PEEP > 5mbar)
Patient requiring curare treatment
Patient requiring ICU after undergoing major surgery (laparotomy or thoracotomy)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

daily consumption of remifentanil between the 24th hour and the 48th hour after randomisation of patients admitted to the ICU and requiring at least 72 hours of mechanical ventilation

Secondary endpoints 13

Cumulative dose of remifentanil
Number of lived days free of remifentanil
Daily consumption of sedative drugs from inclusion to D28
Number of live days free of mechanical ventilation
SOFA Score (Sepsis-related Organ Failure Assessment)
Daily fuid intake in milliliter
CAM ICU test
Presence of one or more events of special interest or expected adverse events: constipation, bradycardia, bladder globe, nausea, vomiting, liver disturbance, serotonin syndrome
Presence of pneumonia associated with mechanical ventilation
Extubation failure and cause (reintubation within 48 hours of first extubation)
Length of stay in the intensive care unit and in the hospital
Vital status at day 28 and day 90
Opioid use at D90

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

KETAMINE RENAUDIN 50 mg/ml, solution injectable

PRD2927934 · Product

Active substance: Ketamine Hydrochloride
Substance synonyms: KET01, KETAMINI HYDROCHLORIDUM, 2-(2-CHLOROPHENYL)-2-METHYLAMINO-CYCLOHEXAN-1-ONE HYDROCHLORIDE
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: INTRAVENOUS USE
Max daily dose: 0.15 mg/kg/h milligram(s)/kilogram/hour
Max total dose: 300 mg milligram(s)
Max treatment duration: 28 Day(s)
Authorisation status: Authorised
ATC code: N01AX03 — KETAMINE
Marketing authorisation: 34009 578 540 2 7
MA holder: LABORATOIRE RENAUDIN
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

TRAMADOL ARROW 100 mg/2 mL, solution injectable/pour perfusion

PRD9891145 · Product

Active substance: Tramadol Hydrochloride
Pharmaceutical form: SOLUTION FOR INJECTION/INFUSION
Route of administration: INTRAVENOUS USE
Max daily dose: 450 mg milligram(s)
Max total dose: 12.6 g gram(s)
Max treatment duration: 28 Week(s)
Authorisation status: Authorised
ATC code: N02AX02 — TRAMADOL
Marketing authorisation: 63777286
MA holder: EUGIA PHARMA (MALTA) LTD
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

PARACETAMOL B BRAUN 10 mg/ml, solution pour perfusion

PRD4398040 · Product

Active substance: Paracetamol
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INTRAVENOUS USE
Max daily dose: 3 g gram(s)
Max total dose: 84 g gram(s)
Max treatment duration: 28 Day(s)
Authorisation status: Authorised
ATC code: N02BE01 — PARACETAMOL
Marketing authorisation: 34009 583 075 2 2
MA holder: B.BRAUN MELSUNGEN AG
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

NEFOPAM VIATRIS 20 mg/2 ml, solution injectable

PRD9486326 · Product

Active substance: Nefopam Hydrochloride
Substance synonyms: AD 337, 5-METHYL-1-PHENYL-1,3,4,6-TETRAHYDRO-2,5-BENZOXAZOCINE HYDROCHLORIDE
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: INTRAVENOUS USE
Max daily dose: 120 mg milligram(s)
Max total dose: 3.6 g gram(s)
Max treatment duration: 28 Day(s)
Authorisation status: Authorised
ATC code: N02BG06 — NEFOPAM
Marketing authorisation: 34009 358 764 9 2
MA holder: VIATRIS SANTE
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

ULTIVA 5 mg, poudre pour solution injectable ou pour perfusion

PRD5214871 · Product

Active substance: Remifentanil Hydrochloride
Pharmaceutical form: POWDER FOR SOLUTION FOR INJECTION/INFUSION
Route of administration: INTRAVENOUS USE
Max daily dose: 0.03 mg/kg/h milligram(s)/kilogram/hour
Max total dose: 0.03 mg/kg/h milligram(s)/kilogram/hour
Max treatment duration: 28 Week(s)
Authorisation status: Authorised
ATC code: N01AH06 — REMIFENTANIL
Marketing authorisation: 34009 560 164 9 5
MA holder: ASPEN PHARMA TRADING LIMITED
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Placebo 1

CHLORURE DE SODIUM 0,9 % AGUETTANT, solution pour perfusion

PRD10486729 · Product

Active substance: Sodium Chloride
Pharmaceutical form: SOLUTION FOR INFUSION
Route of administration: INTRAVENOUS USE
Max daily dose: 600 ml millilitre(s)
Max total dose: 14.6 l litre(s)
Max treatment duration: 28 Week(s)
Authorisation status: Authorised
ATC code: B05XA03 — SODIUM CHLORIDE
Marketing authorisation: 34009 352 291 1 3
MA holder: LABORATOIRE AGUETTANT
MA country: France
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nimes

Sponsor organisation: Centre Hospitalier Universitaire De Nimes
Address: Place Du Professeur Robert Debre
City: Nimes
Postcode: 30900
Country: France

Scientific contact point

Organisation: Centre Hospitalier Universitaire De Nimes
Contact name: Dr remy WIDEHEM

Public contact point

Organisation: Centre Hospitalier Universitaire De Nimes
Contact name: Christophe MASSEGUIN

Locations

1 EU/EEA country · 1 investigational sites

By country

Country	MS status	Planned subjects	Sites
France	Ongoing, recruitment ended	50	1
Rest of world	—	0	—

Investigational sites

France

1 site · Ongoing, recruitment ended

Centre Hospitalier Universitaire De Nimes

+33466683050, Place Du Professeur Robert Debre, 30900, Nimes

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
France	2023-05-10		2023-05-15	2025-01-17

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Temporary halt TH-70871

Halt date: 2025-01-17
Planned restart: 2025-04-01
Member states concerned: France
Publication date: 2025-02-14
Reason: Sponsor decision, Safety related (clinical or pre-clinical results)
Explanation: At this stage, two potential causes for these adverse events have been identified:
1. Considering the short half-life of remifentanil, there may have been a lack of analgesic coverage between the discontinuation of remifentanil and the administration of the tramadol/nefopam mixture in these patients.
2. Rare cases of tachycardia have been reported in the Summary of Product Characteristics (SPC) for both tramadol and nefopam. The observed events could therefore also be a side effect of one of these two active ingredients (nefopam or tramadol) or their combination.
Follow-up measures: There were no specific follow-up measures after resolution of the event for the patients concerned.

For future patients, to address these two potential causes and minimize risks, the following modifications will be introduced into the protocol (substantial modification to be validated):
• The ongoing remifentanil syringe before inclusion will be maintained for the first two hours after randomization and at the start of experimental treatment administration to prevent a lack of analgesia. The remifentanil syringe will be present in both groups for exactly two hours post-randomization. There is no impact on the primary outcome measure (remifentanil dose between the 24th and 48th hour). Measurement bias is avoided by ensuring the same exposure duration in each group.

• The protocol for loading dose administration of nefopam and tramadol will be modified as follow.
Currently, to maintain blinding, the experimental treatment/placebo is prepared by the CHU Nîmes Drug Preparation Unit for the three days of blinded treatment. (Describe current procedure.)
Under the current protocol, a single 100 ml bag of a mixture of Nefopam 20mg and Tramadol 50mg (or placebo) is administered.
The new administration method will involve infusing a 50mL bag containing either 20mg of nefopam or placebo over 30 minutes, followed by a 50mL bag containing either 50mg of tramadol or placebo over 30 minutes. These two infusions will be administered sequentially over one hour, without overlap. Separating the two drugs will help determine whether the adverse events are caused by their combination, one of the two drugs individually, or insufficient analgesia (see previous point).
To limit intravenous sodium and fluid intake, the volume of each bag will be reduced to 50mL. As a result, the total fluid intake remains unchanged compared to the previous protocol.
Benefit-risk balance changed: Yes
Treatment stopped: Yes

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Type	Title	Version
Protocol (for publication)	D1_PROTOCOL_2024-517770-14-00	1.6
Protocol (for publication)	D1_PROTOCOLE_2024-517770-14-00_SM03_trackchange	1.6
Recruitment arrangements (for publication)	D1_Document_additionnel_2024-517770-14-00	1
Subject information and informed consent form (for publication)	L1_SIS and ICF-patient_2024-517770-14-00	1.2
Subject information and informed consent form (for publication)	L1_SIS and ICF-patient_2024-517770-14-00_trackchange	1.2
Subject information and informed consent form (for publication)	L1_SIS and ICF-proche_2024-517770-14-00	1.2
Subject information and informed consent form (for publication)	L1_SIS and ICF-proche_2024-517770-14-00_trackchange	1.2
Summary of Product Characteristics (SmPC) (for publication)	G2_SmPC_ME_KETAMINE_20200408_2024-517770-14-00	1
Summary of Product Characteristics (SmPC) (for publication)	G2_SmPC_ME_NEFOPAM VIATRIS_20220209_2024-517770-14-00	1
Summary of Product Characteristics (SmPC) (for publication)	G2_SmPC_ME_PARACETAMOL BBRAUN_20220830_2024-517770-14-00	1
Summary of Product Characteristics (SmPC) (for publication)	G2_SmPC_ME_REMIFENTANIL ASPEM PHARMA_20231114_2024-517770-14-00	1
Summary of Product Characteristics (SmPC) (for publication)	G2_SmPC_ME_TRAMADOL ARROW_20220823_2024-517770-14-00	1
Synopsis of the protocol (for publication)	D1_PROTOCOL SYNOPSIS_FR_2024-517770-14-00	4
Synopsis of the protocol (for publication)	D1_PROTOCOL SYNOPSIS_V4_FR_2024-517770-14-00_Trackchanges	4

Application history

4 submissions — initial application plus substantial / non-substantial modifications

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2024-09-19	France	Acceptable 2024-10-15	2024-10-17
2	SUBSTANTIAL MODIFICATION	SM-1	2025-03-16	France	Acceptable with conditions 2025-06-23	2025-06-26
3	SUBSTANTIAL MODIFICATION	SM-2	2025-07-04	France	Acceptable with conditions	2025-08-18
4	SUBSTANTIAL MODIFICATION	SM-3	2025-09-15	France	Acceptable 2025-11-14	2025-11-19