SIKAMIC (SIklos on Kidney Function and AlbuMInuria Clinical Trial)

Study Overview
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Brief Summary
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The purpose of this phase IIb, international, multicentre, double-blind, randomised, placebo-controlled study is to determine the effect of hydroxycarbamide on albuminuria after 6 months of treatment in SCD adult patients.

Official Title
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Multicentre Randomized Double-blind Placebo-controlled Study to Evaluate the Effect on Albuminuria of 6 Months Treatment With Hydroxycarbamide (Siklos®) or a Placebo in Adults With Sickle Cell Disease:

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Hydroxycarbamide
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated Informed Consent Form (ICF) by a legally competent patient. Patients above 18 years. Patients with HbSS or HbSβ0 SCD. Patients with a value of albuminuria, assessed by ACR, over 3 mg/mmol and inferior to 100 mg/mmol confirmed by 3 positive urine samples taken one day apart. Female patients of childbearing potential or postmenopausal female with last period < 12 months before screening agreeing to use a highly effective form of contraception (oral, injected or implanted hormonal contraception, intrauterine device, diaphragm, condom) during the trial and for 3 months after hydroxycarbamide discontinuation. Male patients with partners of childbearing potential agreeing to use a highly effective contraception during the trial and for 3 months after hydroxycarbamide discontinuation. Men with pregnant or lactating women should be advised to use a barrier method of contraception (condom) to prevent the foetus or breastfed infant from exposure to hydroxycarbamide. Patients who are covered by insurance scheme according to local regulatory requierements. Exclusion Criteria: Patients who had severe VOC requiring hospitalisation or ACS within the last 4 weeks preceding screening visit. Patients treated with hydroxycarbamide for any reason within the previous 6 months. Patients who have had chronic blood transfusion or transfusion in the last 3 months. Patients with a history of hypertension (systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mmHg) treated with antihypertensive agent belonging to pharmacological class of RAS inhibitor. Patients who have symptoms suggestive of urinary tract infection or patients with gross haematuria. Patients with a concomitant primary kidney disease. Patients with any systemic condition that could result in a glomerulopathy not related to SCD (e.g. diabetes mellitus, active hepatitis B or C infections, HIV infection, systemic lupus erythematosus, inflammatory arthropathies). Patient with a stage 3, 4 or 5 chronic kidney disease (eGFR < 60 mL/min per 1.73 m2). Patients with eGFR ≥ 140 ml/min/1,73m² due to the lack of information regarding the magnitude, direction and significance of the trends in eGFR evolution that could be expected in this population Patients requiring long-term treatment with drugs potentially nephrotoxic (see non-exhaustive list). Patients requiring ACE inhibitors or ARBs within the 3 months before inclusion regardless of the indication. Patients requiring long-term treatment with non-steroid anti-inflammatory drugs. Patients who have a treatment which can modify the kidney function (see non-exhaustive list) in the last 3 months. Patients known to be infected with HIV. Female patients who are pregnant or lactating. Unreliable patients including non-compliant patients, patients with known alcoholism or drug abuse or with a history of a serious psychiatric disorder as well as patients unwilling to give informed consent or to abide by the requirements of the protocol. Simultaneous participation in other clinical trials on an investigational medicinal product or previous participation within 30 days before inclusion. Persons in detention by judicial or administrative decision. Patients with chronic conditions that upon investigator judgment may lead to a limited life expectancy

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxycarbamide<br>Hydroxycarbamide will be supplied as 100 mg or 1000 mg film-coated tablets. The posology will be based on the patient's body weight (bw). Hydroxycarbamide will be prescribed at a dose of 15 mg/kg bw/day and will be adminitered for 6 months. Hydroxycarbamide will be administered for 12 months for patients qualified as responders willing to continue to participate in the trial. | Drug: Hydroxycarbamide<br>* Hydroxycarbamide tablets of 100 and 1000 mg<br>* Other names: Siklos;|
| Placebo Comparator: Placebo<br>Placebo will be supplied as 100 mg or 1000 mg film-coated tablets. The posology will be based on the patient's body weight (bw). Placebo will be prescribed at a dose of 15 mg/kg bw/day and will be adminitered for 6 months. Hydroxycarbamide will be administered for 12 months for patients qualified as responders willing to continue to participate in the trial. | Drug: Placebo Oral Tablet<br>* Placebo tablets of 100 and 1000 mg to mimic hydroxycarbamide tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving at least a 30% decrease in ACR baseline value |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute mean changes in eGFR value |  | 6 months | 
| Absolute mean changes in ACR value |  | 6 months | 
| Proportion of patients with a shift from macroalbuminuria to microalbuminuria |  | 6 months | 
| Proportion of patients with a shift from microalbuminuria to normoalbuminuria |  | 6 months | 
| Proportion of patients with a shift from macroalbuminuria to normoalbuminuria |  | 6 months | 
| Proportion of patients with a shift from microalbuminuria to macroalbuminuria |  | 6 months | 
| Evolution curve of ACR |  | 6 months | 
| Evolution curve of ACR |  | From treatment initiation to month 12, for responder patients willing to continue the study after 6 months. | 
| Evolution curve of eGFR |  | 6 months | 
| Evolution curve of eGFR |  | From treatment initiation to month 12, for responder patients willing to continue the study after 6 months. | 
| Identification of clinical markers associated with response to treatment. | Reported any sickle cell disease related organopathy | 6 months | 
| Identification of biological markers associated with response to treatment. | Haematology: Red blood cell count and Mean Corpuscular Volume, Dense Red Blood Cells, reticulocytes, Hemoglobin, free Hemoglobin and Fetal hemoglobin, Mean Corpuscular Hemoglobin and Mean Corpuscular Hemoglobin Concentration, hematocrit, White Blood Cell counts, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelet counts, endogenous EPO and ferritin concentrations. Blood biochemistry : Renal function: blood Creatinine. Haemolysis biochemical markers: Lactate Deshydrogenase, aspartate aminotransferase, ALT, BUN, conjugated and total bilirubin. | 6 months | 
| Incidence of treatment-emergent AEs and SAEs |  | Through study completion | 
| Absolute mean changes of systolic blood pressure |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes of body mass index |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes of diastolic blood pressure |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes of heart rate measure |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in white blood cells count |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in platelets count |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in mean corpuscular volume |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in mean corpuscular haemoglobin concentration |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in mean corpuscular haemoglobin |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in hemoglobin count |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in foetal hemoglobin count |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in free hemoglobin count |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in Dense red blood cells percentage |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in endogenous erythropoietin count |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in ferritin count |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in lactate dehydrogenase |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in Aspartate aminotransferase |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in Alanine Amino Transferase |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in blood urea nitrogen |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in conjugated bilirubin |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in total bilirubin |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Absolute mean changes in reticulocytes |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Rate of SCD-related clinical events |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 
| Biomarkers predictive of SCN (only French patients) |  | 6 months and 12 months for responder patients willing to continue the study after month 6. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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albuminuria, hydroxycarbamide