Overview
Sponsor-declared trial summary
Phase
Therapeutic use (Phase IV)
Status
Authorised, recruiting
Participants planned
100
Countries
1
Sites
6
Evaluation of the CKD-Epi score to identify a glomerular filtration threshold predictive of morphine failure at usual dosage, using a reference method for assessing renal function: iohexol clearance. All other aspects of the protocol are part of standard care practice.
The main aim of our study is to identify a glomerular filtration threshold (CKD-Epi) predictive of failure of usual-dose morphine in sickle cell patients in vaso-occlusive crisis, to determine the population that would benefit from higher upfront morphine doses (personalized analgesia).
Key facts
- Sponsor
- Centre Hospitalier Regional Universitaire De Tours
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Respiratory Tract Diseases [C08], Phenomena and Processes [G] - Circulatory and Respiratory Physiological Phenomena [G09], Diseases [C] - Pathological Conditions, Signs and Symptoms [C23], Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Cardiovascular Diseases [C14], Health Care [N] - Health Care Facilities, Manpower, and Services [N02]
- Trial duration
- 5 Mar 2026 → ongoing
- Decision date (initial)
- 2025-07-15
- Transition trial
- No
- Low-intervention
- Yes
- Rare-disease indication
- No
- Vulnerable population
- No
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Dose response
The main aim of our study is to identify a glomerular filtration threshold (CKD-Epi) predictive of failure of usual-dose morphine in sickle cell patients in vaso-occlusive crisis, to determine the population that would benefit from higher upfront morphine doses (personalized analgesia).
Secondary objectives 9
- Validate the relationship between clearance of morphine and its metabolites and estimated GFR according to CKD Epi
- Study the relationship between morphine dose administered and estimated GFR
- Study the relationship between plasma exposure to active morphine and analgesic effect: visual numeric scale (VNS), visual analog scale (VAS) and patient global impression of change (PGIC) scale
- Describe the number and dose of co-administered drugs in relation to the estimated GFR
- Describe the frequency and nature of morphine-related adverse events in relation to the estimated GFR
- Analyze variations in estimated GFR between basal and crisis states
- Validate the use of the CKD-Epi formula for estimating GFR in hospitalization for vaso-occlusive crisis with a reference method (iohexol clearance).
- Determine an appropriate morphine regimen for patients who have reached the CKD Epi GFR threshold (primary objective).
- Determine factors associated with treatment failure (depression, fatigue, age, socio-economic level, family and friend support, interval since last attack, erythrocyte transfusions / transfusion exchanges) and validate threshold prediction adjusted for these potential confounding factors.
Conditions and MedDRA coding
Evaluation of the CKD-Epi score to identify a glomerular filtration threshold predictive of morphine failure at usual dosage, using a reference method for assessing renal function: iohexol clearance. All other aspects of the protocol are part of standard care practice.
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 21.0 | PT | 10040641 | Sickle cell anaemia | 100000004850 |
Study design 4 periods
| # | Title | Allocation | Blinding | Roles blinded | Arms |
|---|---|---|---|---|---|
| 1 | Selecting and recruiting research participants Patient screening will be carried out by clinical research nurses in the centers, under the responsibility of the investigators. The investigator will present the study to eligible patients and obtain their consent. Inclusion at the earliest, within 24 hours of patient admission.
|
Not Applicable | None | ||
| 2 | Inclusion After verification of inclusion and non-inclusion criteria, and after obtaining written consent from patients, exhaustive 7-day collection of :
- Pain assessment parameters: VAS and EVN every 4 hours, PGIC every 24 hours
- PCA adjustment parameters: number of boluses administered (with administration schedule) and refused over the first 24 hours, total morphine dose administered (recorded by PCA) every day for 7 days.
- Co-administered analgesics and their doses (paracetamol, nefopam, ketamine, inhaled nitrous oxide for certain treatments). The use of other analgesics such as non-steroidal anti-inflammatory drugs will be authorized and documented, but will not be encouraged by the protocol. An algorithm for pain management in the acute phase of a vaso-occlusive crisis will be provided to each center, and its use will be encouraged to standardize practices (figure 1). Pain associated with treatment will be prevented by the systematic administration of topical Lidocaine-Prilocaine for painful procedures (particularly venipunctures).
- Morphine tolerance parameters: impaired alertness, bradypnea, hypercapnia, pruritus, constipation, acute urinary retention.
The data collected are the usual clinico-biological data (collected as part of care), with the exception of the PGIC score.
|
Not Applicable | None | ||
| 3 | Intervention Within 24 hours of inclusion, blood samples were taken to measure plasma concentrations of morphine, its metabolites M3G and M6G, and iohexol:
o Samples for morphine and its metabolites: 4 samples (T1 to T4), the first at the patient's first routine morning check-up, then 2 samples at 1 and 9 a.m., and finally the last at the patient's routine 24-hour check-up.
o IV injection of 5 mL of iohexol (Omnipaque® 300mg/mL) 5 minutes before the first morning sample, followed by 3 iohexol samples at 5 minutes, 1h and 9h from the injection to calculate iohexol clearance according to a previously described model (Destere, 2022). Samples for iohexol determination will be taken at the same time and in the same tube (7 mL lithium heparinate) as those for morphine and morphine derivatives, in order to avoid venipunctures and blood spoliation.
Thus, 2 of the 4 samples required for the study will be synchronized with the routine morning check-up performed on patients hospitalized for vaso-occlusive crisis or acute chest syndrome, and only 2 additional samples will be imposed by the study.
Other parameters collected: clinical, biological and therapeutic variables usual in sickle-cell patients. In particular, sickle cell therapy (hydroxyurea, exchange transfusion program), frequency of vaso-occlusive crises, existence of proteinuria, hemoglobinemia, hemoglobin S level, liver function, KDIGO score. Socio-demographic variables will also be collected: family, professional/school status, BDI and PROMIS depression scales, fatigue scale, EPICES score (evaluation of precariousness and health inequalities in health examination centers).
Morphine and M6G clearances will be estimated by Bayesian methods using Monolix software, based on pharmacokinetic parameters and their variability. Briefly, this is a 3-compartment model for morphine and a 2-compartment model for M6G. In sickle-cell patients in crisis, the individual information obtained from 4 samples will be sufficient to adequately estimate individual clearances.
|
Not Applicable | None | ||
| 4 | Follow-up Follow-up will take place for 7 days after inclusion, or will end earlier if the patient leaves the ward before D7. Pain parameters (VAS, EVN) will be collected every 4 hours, and the PGIC score every 24 hours. Every day, the analgesics administered and their dosage will be recorded, and during the 24 hours when samples are taken for morphine dosage, an exhaustive record of morphine boluses through the PCA will be made. Any adverse effects of morphine will also be recorded. In addition, the usual clinico-biological parameters recorded in the care of these patients will be recorded.
|
Not Applicable | None |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 7
- Patient ≥ 18 years
- Known homozygous sickle cell disease SS, SC, S-beta+ or S-beta0
- Admitted to a Continuous Care Unit (CCU) or intensive care unit.
- Clinical diagnosis of vaso-occlusive crisis and/or acute chest syndrome
- Receiving morphine PCA therapy
- Obtained consent to participate in the study and/or from a parent/relative in the event of patient incapacity
- Affiliation with a social securitý scheme.
Exclusion criteria 8
- Patient included in the study during a previous stay
- Injection of iodinated contrast medium outside the study in the 24 hours prior to inclusion, or scheduled within 9 hours of the scheduled time of iohexol injection.
- Contraindication to iohexol: known or suspected immediate or delayed hypersensitivitý, thyrotoxicosis
- Patient on morphine therapy or methadone- or buprenorphine-type substitution therapy, prior to hospitalization (having received morphine or derivative by any route in the week preceding hospitalization)
- Chronic liver disease likely to interfere with morphine metabolism (cirrhosis stage)
- Patient under legal protection
- Pregnant or breast-feeding woman
- Any condition constituting a contraindication to the use of morphine according to the summary of product characteristics
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- The primary endpoint was the area under the ROC curve for prediction of therapeutic failure by GFR according to CKD Epi. Therapeutic failure is defined by a percentage of relief assessed by EVN (numerical verbal scale) not reaching 30% in 24h (Darbari, 2017).
Secondary endpoints 6
- Clearance of morphine and its metabolites M3G and M6G
- Total morphine dose administered over 24 hours and 7 days
- Evolution of pain by EVN and EVA (delta over 24h) and PGIC scale at 24h follow-up
- Patient-controlled analgesia (PCA) regimen and other coadministered analgesics
- Morphine side effects, including impaired alertness, bradypnea, hypercapnia, pruritus, constipation, bloating, nausea, vomiting, acute urinary retention
- Correlation between GFR estimated by CKD Epi in basal st
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 1
MORPHINE (CHLORHYDRATE) RENAUDIN 1 mg/ml, solution injectable
PRD2936270 · Product
- Active substance
- Morphine Hydrochloride
- Substance synonyms
- MORPHINI HYDROCHLORIDUM
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INJECTION
- Max daily dose
- 300 mg/ml milligram(s)/millilitre
- Max total dose
- 300 mg/ml milligram(s)/millilitre
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- N02AA01 — MORPHINE
- Marketing authorisation
- 34009 369 017 5 9
- MA holder
- LABORATOIRE RENAUDIN
- MA country
- France
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Auxiliary 1
Iohexol 300 mg I/ml solution for injection
PRD7770671 · Product
- Active substance
- Iohexol
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- INJECTION
- Max daily dose
- 300 mg/ml milligram(s)/millilitre
- Max total dose
- 300 mg/ml milligram(s)/millilitre
- Max treatment duration
- 1 Day(s)
- Authorisation status
- Authorised
- ATC code
- V08AB02 — IOHEXOL
- Marketing authorisation
- PL 17780/0900
- MA holder
- ZENTIVA PHARMA UK LIMITED
- MA country
- XI
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Centre Hospitalier Regional Universitaire De Tours
- Sponsor organisation
- Centre Hospitalier Regional Universitaire De Tours
- Address
- 2 Boulevard Tonnelle
- City
- Tours Cedex 9
- Postcode
- 37044
- Country
- France
Scientific contact point
- Organisation
- Centre Hospitalier Regional Universitaire De Tours
- Contact name
- Dr Charlotte SALMON GANDONNIERE
Public contact point
- Organisation
- Centre Hospitalier Regional Universitaire De Tours
- Contact name
- Dr Charlotte SALMON GANDONNIERE
Locations
1 EU/EEA country · 6 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| France | Authorised, recruiting | 100 | 6 |
| Rest of world | — | 0 | — |
Investigational sites
Centre Hospitalier Regional Universitaire De Tours
Intensive care, 2 Boulevard Tonnelle, 37000, Tours
Centre Hospitalier Universitaire D Orleans
Intensive care, 14 Avenue De L Hopital, Cs 86709, Orleans Cedex 2
Centre Hospitalier Universitaire De Nantes
Intensive care, 30 Boulevard Jean Monnet, 44000, Nantes
Centre Hospitalier Le Mans
Intensive care, 194 Avenue Rubillard, 72037, Le Mans Cedex 9
Centre Hospitalier Universitaire De Rennes
Intensive care, 2 Rue Henri Le Guilloux, 35000, Rennes
Assistance Publique Hopitaux De Paris
Intensive Care, 51 Avenue Du Mal De Lattre De Tassigny, 94010, Creteil Cedex
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 | 2026-03-05 |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 9 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocole redacted sign 2024_511985_34_00 | 1.3 |
| Recruitment arrangements (for publication) | K1_Recruitment arrangements | 1 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF | 2.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF continuation | 1.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF family | 2.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF family_TC | 2.0 |
| Subject information and informed consent form (for publication) | L1_SIS and ICF_TC | 2.0 |
| Summary of Product Characteristics (SmPC) (for publication) | G2_SmPC_RCP Morphine | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol synopsis_v1_0 2024_511985_34_00 | 1.3 |
Application history
2 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2025-04-01 | France | Acceptable 2025-07-11
|
2025-07-15 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2025-09-19 | France | Acceptable | 2025-10-08 |