Personalized Spacing of Eculizumab Infusions Based on Therapeutic Pharmacological Monitoring (EspacECU)

Study Overview
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Brief Summary
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Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients but several studies have shown a high interindividual kinetics variability. A tailored administration of eculizumab based on therapeutic drug monitoring will be compared with real-life administration in adults suffering from an atypical haemolytic uraemic syndrome. The objective is to improve efficiency of eculizumab administration.

Detailed Description
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Eculizumab is a very expensive drug (450 000 euros per year per patient). According to the usual administration scheme, the eculizumab is administrated by intravenous infusion, every 14 or 21 days in hospital. Studies have shown the possibility of extending the administration intervals in patients with a high concentration of eculizumab. A personalized spacing of eculizumab infusions, based on a therapeutic drug monitoring, is expected to improve the patient's quality of life and lead to substantial savings. For these reasons, the objective of this study is to explore the efficiency of a personalized spacing of eculizumab infusions compared to the usual administration scheme (without personalization) from the French health Insurance perspective. The efficiency will be assessed by estimating the incremental cost per QALY (Quality-Adjusted Life Year) gained at 18 months (duration of follow-up in the clinical trial) and at 5 years thanks to a Markov model. The total duration of the study is 24 months (6 months of enrolment and 18 months of follow-up).

Official Title
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Personalized Spacing of Eculizumab Infusions Based on Therapeutic Pharmacological Monitoring: Prospective Health-economic Evaluation in Patients in Remission With Atypical Hemolytic Uraemic Syndrome Requiring Long-term Treatment.

Conditions
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Hemolytic-Uremic Syndrome, Atypical

Intervention / Treatment
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* Drug: Spacing of Eculizumab infusions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults with an atypical Hemolytic and Uremic Syndrome defined by at least 2 of the following parameters: Thrombopenia (platelet count < 150 G/L) Mechanical lytic anemia (Hb < 10 g/L, Lactate dehydrogenase > upper limit of normal, undetectable haptoglobin, presence of schistocytes on blood smear) Acute renal failure Eculizumab treatment Without project of withdrawal in the next 18 months Started since at least 6 months Administrated with an unchanged administration schedule since at least 3 months (initial episode or relapse) Atypical Hemolytic and Uremic Syndrome in remission Patients who give informed consent. Exclusion Criteria: Patients on dialysis. Women treated starting or planning a pregnancy. Patients suffering from a typical or secondary microangiopathic hemolytic anemia (drugs, malignancies, autoimmune disease...) Patients under protection of a judicial authority

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic drug monitoring<br>Tailored dosing schedule for eculizumab based on therapeutic drug monitoring | Drug: Spacing of Eculizumab infusions<br>* Personalized spacing of eculizumab infusions using a pharmacokinetic population model to estimate eculizumab concentration ( a one-week spacing of eculizumab infusion will be decide if predicted eculizumab concentration in the event of spacing is > 150 mg/L). Spacing of infusion can be decided every 3 months.<br>|
| No Intervention: Control<br>Initial eculizumab schedule is continued (real-life arm). No eculizumab dosages are performed in this arm. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incremental Cost-Utility Ratio (ICUR) at 18 months of a personalized spacing of eculizumab infusions compared to the usual administration scheme without personalization, from the French health insurance perspective. | The ICUR will express the incremental cost per QALY (Quality-adjusted Life Years) gained over a 18-month time horizon. QALYs will be estimated from patient responses to the EQ-5D-5L instrument (EuroQol group - 5 Dimensions - 5 levels). Costs related to hospital care resources (medicalized information system program), transports (patient diary), eculizumab concentration dosing (cost estimation) will be estimated from the French Health Insurance perspective. Cost and QALY estimates will be used to estimate the within-trial ICUR. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incremental Cost-Utility Ratio at 5 years (incremental cost per QALY gained) of a personalized spacing of the eculizumab infusions compared to the usual administration scheme without personalization, estimated from a Markov model. | A Markov model will represent the patient's clinical progression across different health states over a 5-year period. Markov modelling will use the within-trial data to estimate the transition probabilities, the state cost and utility values. | 5 years | 
| Financial impact per year and over a 5-year period of a personalized spacing of eculizumab infusions | The financial impact of spreading the strategy of personalized spacing of eculizumab infusions, in patients in remission with atypical hemolytic uraemic syndrome requiring long-term treatment, will be estimated per year and over a 5-year period, from the French Health Insurance (using a budget impact model). | per year and over a 5-year period | 
| Quality of life measured over a 18-month period using different specific scales (KDQoL-SF, ReTransQoL-Version 2) dedicated to patients with renal disease | KDQoL-SF (Kidney Disease and Quality of Life™ Short Form) survey is a kidney-disease-specific quality of life instrument that assesses four domains : health, kidney disease, effects of kidney disease on daily life, satisfaction with care. Scores for each dimension are reported within the range 0-100, higher scores indicating better health- related quality of life. RTQ-V2 (ReTransQoL-Version 2) survey is a specific quality of life instrument for renal transplant recipients. It comprises of 32 items describing five domains: Physical Health, Social Functioning, Medical Care, Treatment and Fear of Losing Graft. Scores for each dimension are reported within the range 0-100, higher scores indicating better health- related quality of life. KDQoL-SF survey will be used for all patients, and RTQ-V2 survey for kidney transplant patients only. The quality of life will be measured every three months. | at baseline, 3, 6, 9, 12, 15 and 18 months. | 
| Determining the factors of intra- and inter- individual variability of eculizumab concentrations. | A study will be performed to determine whether biological and genetic (complement genetic variants reported as cause of HUS) parameters influence trough concentrations of eculizumab | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemolytic-Uremic Syndrome, Kidney Diseases, Thrombotic Microangiopathies, Therapeutic drug monitoring, Eculizumab tailoring, Cost-utility analysis, Markov model