Evaluation of Morphine Hydrochloride Clearance and Glomerular Filtration Rate in Sickle Cell Disease Patients During Vaso-Occlusive Crisis Using Iohexol.

The primary objective of this study is to identify a **glomerular filtration** threshold using the CKD-Epi formula that predicts the failure of usual-dose **morphine** in patients with sickle cell disease experiencing a vaso-occlusive crisis. This threshold will help determine which patients may benefit from higher initial doses of morphine, thereby enabling personalized analgesia. This is clinically relevant as it aims to optimize pain management in a population with specific renal function challenges, potentially improving patient outcomes and reducing the risk of inadequate pain control.

Secondary objectives include:

• Validating the relationship between the clearance of morphine and its metabolites and the estimated GFR according to CKD-Epi.
• Studying the relationship between the administered morphine dose and estimated GFR.
• Examining the relationship between plasma exposure to active morphine and its analgesic effect using scales such as the visual numeric scale (VNS), visual analog scale (VAS), and patient global impression of change (PGIC) scale.
• Describing the number and dose of co-administered drugs in relation to the estimated GFR.
• Describing the frequency and nature of morphine-related adverse events in relation to the estimated GFR.
• Analyzing variations in estimated GFR between basal and crisis states.
• Validating the use of the CKD-Epi formula for estimating GFR during hospitalization for vaso-occlusive crisis with a reference method (iohexol clearance).
• Determining an appropriate morphine regimen for patients who have reached the CKD-Epi GFR threshold.
• Identifying factors associated with treatment failure, such as depression, fatigue, age, socio-economic level, family and friend support, interval since last attack, and erythrocyte transfusions, and validating threshold prediction adjusted for these potential confounding factors.

The clinical trial involves a study population of **adults** aged 18 years and older, comprising both **male** and **female** participants. The trial focuses on individuals with known homozygous **sickle cell disease** (SS, SC, S-beta+, or S-beta0) who are admitted to a Continuous Care Unit or intensive care unit. Participants are experiencing a vaso-occlusive crisis and/or acute chest syndrome and are receiving morphine PCA therapy. The study aims to identify a glomerular filtration threshold predictive of morphine failure at usual dosages, using iohexol clearance as a reference method for assessing renal function. The sponsor has not provided the total number of participants. Participants were selected based on their clinical diagnosis and treatment regimen, with consent obtained from the patient or a relative in cases of incapacity. The trial does not include a vulnerable population, and all participants are affiliated with a social security scheme. Lifestyle considerations such as diet and physical activity are not specified in the provided data.

The clinical trial is designed to evaluate the **glomerular filtration rate (GFR)** threshold predictive of therapeutic failure of usual-dose **morphine** in patients with sickle cell disease experiencing a vaso-occlusive crisis. This study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to commence on July 1, 2025, and conclude by January 1, 2028, with the primary objective of identifying patients who may benefit from personalized analgesia through higher upfront doses of morphine.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are confirmed. Key inclusion criteria include being 18 years or older, having a known diagnosis of homozygous sickle cell disease, and being admitted to a continuous care or intensive care unit with a clinical diagnosis of vaso-occlusive crisis or acute chest syndrome. Participants must also be receiving morphine PCA therapy and provide consent to participate. The inclusion visit will involve screening procedures to assess the patient's medical history and current health status.

Following the inclusion visit, participants will attend follow-up visits to monitor the clearance of morphine and its metabolites, as well as the total morphine dose administered over 24 hours and 7 days. These visits will also evaluate the evolution of pain using the numerical verbal scale (EVN) and the patient global impression of change (PGIC) scale. The primary endpoint is the area under the ROC curve for predicting therapeutic failure by GFR according to the CKD-Epi score, with therapeutic failure defined as less than 30% relief in 24 hours.

The end-of-study visit will occur at the conclusion of the trial, where final assessments will be conducted to evaluate the overall effectiveness and safety of the treatment regimen. The expected length of participant involvement is approximately one year, with conditions for early termination including withdrawal of consent, adverse events, or any significant protocol deviations. The study aims to provide valuable insights into the management of pain in sickle cell patients, potentially leading to improved therapeutic strategies.

The clinical trial involves the administration of **Morphine Hydrochloride** as the experimental medication. The product used is "MORPHINE (CHLORHYDRATE) RENAUDIN 1 mg/ml, solution injectable," manufactured by LABORATOIRE RENAUDIN. This pharmaceutical form is a **solution for injection**, with a concentration of 1 mg/ml. The route of administration is via injection. The maximum daily dose and total dose amount are both set at 300 mg/ml, with a maximum treatment period of one day. The active substance, morphine hydrochloride, is of chemical origin and is classified under the ATC code N02AA01. This medication is not a pediatric formulation and is not designated as an orphan drug.

In addition to the experimental treatment, the trial also utilizes **Iohexol** as an auxiliary substance. The product "Iohexol 300 mg I/ml solution for injection" is provided by ZENTIVA PHARMA UK LIMITED. This solution for injection contains iohexol as the active substance, also of chemical origin, and is classified under the ATC code V08AB02. The concentration of iohexol is 300 mg/ml, with the same maximum daily and total dose limits as the morphine hydrochloride, and a maximum treatment period of one day. This product is similarly not a pediatric formulation and does not have orphan drug status.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the area under the ROC curve for the prediction of therapeutic failure by glomerular filtration rate (GFR) according to the CKD-Epi formula. Therapeutic failure is defined as a percentage of relief assessed by the numerical verbal scale (EVN) not reaching 30% within 24 hours.

Secondary endpoints include the clearance of **morphine** and its metabolites M3G and M6G, the total morphine dose administered over 24 hours and 7 days, and the evolution of pain as measured by EVN and EVA (delta over 24 hours) and the PGIC scale at 24-hour follow-up. Additional secondary endpoints involve the patient-controlled analgesia (PCA) regimen, other coadministered analgesics, and morphine side effects such as impaired alertness, bradypnea, hypercapnia, pruritus, constipation, bloating, nausea, vomiting, and acute urinary retention. The correlation between GFR estimated by CKD-Epi and baseline status will also be evaluated.