Sickle Cell Disease
Conditions
Keywords
albuminuria, hydroxycarbamide
Brief summary
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.
Interventions
DRUGHydroxycarbamide
Hydroxycarbamide tablets of 100 and 1000 mg
DRUGPlacebo Oral Tablet
Placebo tablets of 100 and 1000 mg to mimic hydroxycarbamide tablets
Sponsors
Theravia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed and dated Informed Consent Form (ICF) by a legally competent patient. 2. Patients above 18 years. 3. Patients with HbSS or HbSβ0 SCD. 4. 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. 5. 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. 6. 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. 7. Patients who are covered by insurance scheme according to local regulatory requierements.
Exclusion criteria
1. Patients who had severe VOC requiring hospitalisation or ACS within the last 4 weeks preceding screening visit. 2. Patients treated with hydroxycarbamide for any reason within the previous 6 months. 3. Patients who have had chronic blood transfusion or transfusion in the last 3 months. 4. 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. 5. Patients who have symptoms suggestive of urinary tract infection or patients with gross haematuria. 6. Patients with a concomitant primary kidney disease. 7. 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). 8. Patient with a stage 3, 4 or 5 chronic kidney disease (eGFR \< 60 mL/min per 1.73 m2). 9. 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 10. Patients requiring long-term treatment with drugs potentially nephrotoxic (see non-exhaustive list). 11. Patients requiring ACE inhibitors or ARBs within the 3 months before inclusion regardless of the indication. 12. Patients requiring long-term treatment with non-steroid anti-inflammatory drugs. 13. Patients who have a treatment which can modify the kidney function (see non-exhaustive list) in the last 3 months. 14. Patients known to be infected with HIV. 15. Female patients who are pregnant or lactating. 16. 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. 17. Simultaneous participation in other clinical trials on an investigational medicinal product or previous participation within 30 days before inclusion. 18. Persons in detention by judicial or administrative decision. 19. Patients with chronic conditions that upon investigator judgment may lead to a limited life expectancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Achieving at Least a 30% Decrease in ACR Baseline Value | 6 months | The primary endpoint of this study is the proportion of patients in the hydroxycarbamide and placebo groups achieving at least a 30% decrease in ACR baseline value at 6 months after treatment initiation. Patients who do not achieve at least a 30% decrease of the ACR baseline value at month 6 will be considered non-responders. |
Secondary
| Measure | 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 |
| Absolute Mean Changes of Systolic Blood Pressure | 6 months |
| Absolute Mean Changes of Body Weight | 6 months |
| Absolute Mean Changes of Diastolic Blood Pressure | 6 months |
| Absolute Mean Changes of Heart Rate Measure | 6 months |
| Absolute Mean Changes in White Blood Cells Count | 6 months |
| Absolute Mean Changes in Platelets Count | 6 months |
| Absolute Mean Changes in Mean Corpuscular Volume | 6 months |
| Absolute Mean Changes in Mean Corpuscular Haemoglobin Concentration | 6 months |
| Absolute Mean Changes in Mean Corpuscular Haemoglobin | 6 months |
| Absolute Mean Changes in Hemoglobin Count | 6 months |
| Absolute Mean Changes in Foetal Hemoglobin Count | 6 months |
| 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 |
| Absolute Mean Changes in Ferritin Count | 6 months |
| Absolute Mean Changes in Lactate Dehydrogenase | 6 months |
| Absolute Mean Changes in Aspartate Aminotransferase | 6 months |
| Absolute Mean Changes in Alanine Amino Transferase | 6 months |
| Absolute Mean Changes in Blood Urea Nitrogen | 6 months |
| Absolute Mean Changes in Conjugated Bilirubin | 6 months |
| Absolute Mean Changes in Total Bilirubin | 6 months |
| Absolute Mean Changes in Reticulocytes | 6 months |
Countries
Côte d’Ivoire, France, Guadeloupe, Mali, Martinique, Senegal
Participant flow
Recruitment details
From 28 May 2019 to 30 May 2024, 86 patients were included in the study in the mITT population and analysed in France and Africa (Mali, Ivory Coast and Senegal).
Participants by arm
| Arm | Count |
|---|---|
| Hydroxycarbamide 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.
Hydroxycarbamide: Hydroxycarbamide tablets of 100 and 1000 mg | 46 |
| Placebo 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.
Placebo Oral Tablet: Placebo tablets of 100 and 1000 mg to mimic hydroxycarbamide tablets | 40 |
| Total | 86 |
Baseline characteristics
| Characteristic | Placebo | Hydroxycarbamide | Total |
|---|---|---|---|
| Age, Continuous | 30.0 years STANDARD_DEVIATION 8.7 | 30.3 years STANDARD_DEVIATION 10 | 30.2 years STANDARD_DEVIATION 9.3 |
| Race/Ethnicity, Customized Continent of origin Africa - America | 40 Participants | 45 Participants | 85 Participants |
| Race/Ethnicity, Customized Continent of origin Other | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Côte D'Ivoire | 4 participants | 5 participants | 9 participants |
| Region of Enrollment France | 15 participants | 11 participants | 26 participants |
| Region of Enrollment Guadeloupe | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Mali | 8 participants | 12 participants | 20 participants |
| Region of Enrollment Martinique | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Senegal | 12 participants | 17 participants | 29 participants |
| SCD genotype HbSbeta0 | 3 Participants | 3 Participants | 6 Participants |
| SCD genotype HbSS | 37 Participants | 43 Participants | 80 Participants |
| Sex: Female, Male Female | 27 Participants | 32 Participants | 59 Participants |
| Sex: Female, Male Male | 13 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 2 / 40 |
| other Total, other adverse events | 30 / 46 | 29 / 40 |
| serious Total, serious adverse events | 5 / 46 | 7 / 40 |
Outcome results
Primary
Number of Patients Achieving at Least a 30% Decrease in ACR Baseline Value
The primary endpoint of this study is the proportion of patients in the hydroxycarbamide and placebo groups achieving at least a 30% decrease in ACR baseline value at 6 months after treatment initiation. Patients who do not achieve at least a 30% decrease of the ACR baseline value at month 6 will be considered non-responders.
Time frame: 6 months
Population: 3 patients in the hydroxycarbamide arm and 2 patients in the placebo arm do not have any measure at 6 months and so were not part of this analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxycarbamide | Number of Patients Achieving at Least a 30% Decrease in ACR Baseline Value | 18 Participants |
| Placebo | Number of Patients Achieving at Least a 30% Decrease in ACR Baseline Value | 15 Participants |
Secondary
Absolute Mean Changes in ACR Value
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in ACR Value | 3.5 mg/mmol | Standard Error 19.7 |
| Placebo | Absolute Mean Changes in ACR Value | 1.0 mg/mmol | Standard Error 13.1 |
Secondary
Absolute Mean Changes in Alanine Amino Transferase
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Alanine Amino Transferase | -1.7 U/L | Standard Deviation 51.2 |
| Placebo | Absolute Mean Changes in Alanine Amino Transferase | -0.2 U/L | Standard Deviation 13.7 |
Secondary
Absolute Mean Changes in Aspartate Aminotransferase
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Aspartate Aminotransferase | -8.7 U/L | Standard Deviation 19.2 |
| Placebo | Absolute Mean Changes in Aspartate Aminotransferase | -1.0 U/L | Standard Deviation 10.9 |
Secondary
Absolute Mean Changes in Blood Urea Nitrogen
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Blood Urea Nitrogen | -0.5 mmol/L | Standard Deviation 6.4 |
| Placebo | Absolute Mean Changes in Blood Urea Nitrogen | 0.5 mmol/L | Standard Deviation 2.6 |
Secondary
Absolute Mean Changes in Conjugated Bilirubin
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Conjugated Bilirubin | -0.7 µmol/L | Standard Deviation 33.8 |
| Placebo | Absolute Mean Changes in Conjugated Bilirubin | -1.9 µmol/L | Standard Deviation 9.8 |
Secondary
Absolute Mean Changes in Dense Red Blood Cells Percentage
Time frame: 6 months and 12 months for responder patients willing to continue the study after month 6.
Secondary
Absolute Mean Changes in eGFR Value
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in eGFR Value | 3.2 ml/min/1.73m2 | Standard Deviation 18.5 |
| Placebo | Absolute Mean Changes in eGFR Value | -1.0 ml/min/1.73m2 | Standard Deviation 13.8 |
Secondary
Absolute Mean Changes in Endogenous Erythropoietin Count
Time frame: 6 months
Population: Very few patients have an evaluation of endogenous erythropoietin count. Only 3 in hydroxycarbamide group and 6 in placebo group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Endogenous Erythropoietin Count | -8.2 U/L | Standard Deviation 22.1 |
| Placebo | Absolute Mean Changes in Endogenous Erythropoietin Count | 17.4 U/L | Standard Deviation 37.1 |
Secondary
Absolute Mean Changes in Ferritin Count
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Ferritin Count | 28.1 µg/L | Standard Deviation 664.2 |
| Placebo | Absolute Mean Changes in Ferritin Count | -8.0 µg/L | Standard Deviation 404.3 |
Secondary
Absolute Mean Changes in Foetal Hemoglobin Count
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Foetal Hemoglobin Count | 8.5 percentage of hemoglobin | Standard Deviation 8.8 |
| Placebo | Absolute Mean Changes in Foetal Hemoglobin Count | 0.3 percentage of hemoglobin | Standard Deviation 1.9 |
Secondary
Absolute Mean Changes in Free Hemoglobin Count
Time frame: 6 months and 12 months for responder patients willing to continue the study after month 6.
Secondary
Absolute Mean Changes in Hemoglobin Count
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Hemoglobin Count | 12 g/L | Standard Deviation 11.3 |
| Placebo | Absolute Mean Changes in Hemoglobin Count | -2.2 g/L | Standard Deviation 6.1 |
Secondary
Absolute Mean Changes in Lactate Dehydrogenase
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Lactate Dehydrogenase | -170.5 U/L | Standard Deviation 349.4 |
| Placebo | Absolute Mean Changes in Lactate Dehydrogenase | -1.8 U/L | Standard Deviation 220.9 |
Secondary
Absolute Mean Changes in Mean Corpuscular Haemoglobin
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Mean Corpuscular Haemoglobin | 5.5 pg | Standard Deviation 4 |
| Placebo | Absolute Mean Changes in Mean Corpuscular Haemoglobin | -0.8 pg | Standard Deviation 1.6 |
Secondary
Absolute Mean Changes in Mean Corpuscular Haemoglobin Concentration
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Mean Corpuscular Haemoglobin Concentration | 1.7 g/L | Standard Deviation 15.8 |
| Placebo | Absolute Mean Changes in Mean Corpuscular Haemoglobin Concentration | -4.8 g/L | Standard Deviation 16.4 |
Secondary
Absolute Mean Changes in Mean Corpuscular Volume
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Mean Corpuscular Volume | 15.1 fL | Standard Deviation 10.8 |
| Placebo | Absolute Mean Changes in Mean Corpuscular Volume | -0.3 fL | Standard Deviation 3.4 |
Secondary
Absolute Mean Changes in Platelets Count
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Platelets Count | -49.3 10^9 platelets per liter | Standard Deviation 150.9 |
| Placebo | Absolute Mean Changes in Platelets Count | -16.0 10^9 platelets per liter | Standard Deviation 83.5 |
Secondary
Absolute Mean Changes in Reticulocytes
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Reticulocytes | -116082.5 cells/mm3 | Standard Deviation 168548.6 |
| Placebo | Absolute Mean Changes in Reticulocytes | -35336.1 cells/mm3 | Standard Deviation 108156.3 |
Secondary
Absolute Mean Changes in Total Bilirubin
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in Total Bilirubin | -8.9 µmol/L | Standard Deviation 106.5 |
| Placebo | Absolute Mean Changes in Total Bilirubin | 4.7 µmol/L | Standard Deviation 30.1 |
Secondary
Absolute Mean Changes in White Blood Cells Count
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes in White Blood Cells Count | -3659.6 cells/mm3 | Standard Deviation 3524.4 |
| Placebo | Absolute Mean Changes in White Blood Cells Count | -228.4 cells/mm3 | Standard Deviation 2982.1 |
Secondary
Absolute Mean Changes of Body Weight
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes of Body Weight | 2.2 kg | Standard Deviation 3 |
| Placebo | Absolute Mean Changes of Body Weight | -0.3 kg | Standard Deviation 2.1 |
Secondary
Absolute Mean Changes of Diastolic Blood Pressure
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes of Diastolic Blood Pressure | 2.5 mmHg | Standard Deviation 13.3 |
| Placebo | Absolute Mean Changes of Diastolic Blood Pressure | -1.0 mmHg | Standard Deviation 12.9 |
Secondary
Absolute Mean Changes of Heart Rate Measure
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes of Heart Rate Measure | -2.1 beats/minute | Standard Deviation 11.3 |
| Placebo | Absolute Mean Changes of Heart Rate Measure | 2.4 beats/minute | Standard Deviation 12.5 |
Secondary
Absolute Mean Changes of Systolic Blood Pressure
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hydroxycarbamide | Absolute Mean Changes of Systolic Blood Pressure | 2.8 mmHg | Standard Deviation 10.7 |
| Placebo | Absolute Mean Changes of Systolic Blood Pressure | 2.2 mmHg | Standard Deviation 13.1 |
Secondary
Proportion of Patients With a Shift From Macroalbuminuria to Microalbuminuria
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxycarbamide | Proportion of Patients With a Shift From Macroalbuminuria to Microalbuminuria | 1 Participants |
| Placebo | Proportion of Patients With a Shift From Macroalbuminuria to Microalbuminuria | 2 Participants |
Secondary
Proportion of Patients With a Shift From Macroalbuminuria to Normoalbuminuria
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxycarbamide | Proportion of Patients With a Shift From Macroalbuminuria to Normoalbuminuria | 1 Participants |
| Placebo | Proportion of Patients With a Shift From Macroalbuminuria to Normoalbuminuria | 0 Participants |
Secondary
Proportion of Patients With a Shift From Microalbuminuria to Macroalbuminuria
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxycarbamide | Proportion of Patients With a Shift From Microalbuminuria to Macroalbuminuria | 3 Participants |
| Placebo | Proportion of Patients With a Shift From Microalbuminuria to Macroalbuminuria | 3 Participants |
Secondary
Proportion of Patients With a Shift From Microalbuminuria to Normoalbuminuria
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxycarbamide | Proportion of Patients With a Shift From Microalbuminuria to Normoalbuminuria | 10 Participants |
| Placebo | Proportion of Patients With a Shift From Microalbuminuria to Normoalbuminuria | 7 Participants |