Nephropathy, Sickle Cell Anemia
Conditions
Brief summary
Sickle cell disease causes kidney damage with increasing age, leading to chronic kidney disease and renal failure in nearly one third of patients with sickle cell disease. Currently, there is no treatment for sickle cell related kidney disease.
Detailed description
The purpose of this research study is to see if losartan can help reduce or reverse damage done to the kidneys of children and adults with Sickle Cell Anemia (SCA) and Sickle Beta-zero (HbSβ0) Thalassemia.
Interventions
DRUGLosartan
Form: suspension, tablet. Dosage & frequency: age 6-16 = 0.7mg/kg once daily; age \>16 = 50mg once daily. Duration: 6 months
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥6 years of age; for no albuminuria (NoA) group age is ≥ 6 years and \<21 years of age 2. Diagnosis of hemoglobin SS disease or Sβ0 thalassemia by hemoglobin electrophoresis and/or β-globin gene mapping. 3. Urine osmolality \<700 mOsm (milliosmoles) on first morning urine 4. Written informed consent (and assent, where applicable) 5. Documented urine albumin to creatinine ratio (UACR) showing either * NoA: UACR \<30mg/g creatinine on a first morning urine * MiA: UACR 30-300 mg/g creatinine on a first morning urine or * MaA: UACR \>300 mg/g creatinine on a first morning urine sample 6. A documented negative serum pregnancy test for females with child bearing potential or greater than 10 years of age within (prior to) 7 days of starting the study medication. 7. Subjects with child-bearing potential must be willing to use a medically accepted form of contraception throughout the study. 8. Patients on hydroxyurea (HU) who are on a stable (not changing) dose of HU for three months prior to study entry.
Exclusion criteria
1. Patients with Hb SC, SD, Sβ+thal, SE and other sickle hemoglobinopathies, and sickle trait (AS). 2. Pregnant or lactating females, or females of child-bearing potential that are unable to use a medically accepted form of contraception throughout the study. 3. Urine creatinine clearance (Clcr) \<60 mL/minute/1.73 m2 4. Gross (not microscopic) hematuria. If hematuria has resolved for 2 weeks or more, patients will be eligible. 5. Hyperkalemia (K≥5.5) at baseline despite a low potassium diet 6. Concurrent condition that predisposes to nephropathy, such as lupus, diabetes, and hypertension, not controlled with medications.. 7. On a renin-angiotensin pathway inhibitor (e.g., captopril, lisinopril, Losartan, valsartan, etc) for the last two weeks prior to enrollment. 8. Hypersensitivity to Angiotensin II receptor blockers such as losartan, valsartan, telmisartan. 9. Patients on red cell apheresis or ongoing aggressive chronic transfusions (one or more a month with a goal of HbS \< 30%). Patients receiving a simple transfusion for symptoms during acute event will be eligible, but if they receive a partial or full exchange transfusion during an acute event, then they will only be eligible after 90 days. 10. Hepatic dysfunction defined as ALT (alanine aminotransferase) or direct bilirubin \> 3-times upper limit of normal (ULN). 11. Chronic therapy with NSAIDS or Cox2 inhibitors 12. On another interventional trial. May be eligible two weeks after completion of another interventional study. 13. Any condition that interferes with the ability of the patient to understand or comply with the treatment plan and follow up. 14. A serious mental or physical illness or a major disease (cardiac, renal, hepatic, neurological, endocrine, metabolic, pulmonary function or psychiatric), which in the opinion of the investigator would compromise participation in the study. 15. Unable to take oral medications. 16. HIV confirmed positive. 17. Chronic therapy with steroids. May be eligible after three weeks of completing steroid therapy. 18. Patients on lithium will be excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Categorical Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline | Baseline and 6 months | Number of participants who have a ≥25% reduction in urinary albumin-to-creatinine ratio (UACR) from baseline to 6 months. This is a categorical outcome (yes/no). We hypothesized and pre-specified that ≥30% of the subjects in the microalbuminuria group would meet this outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in UACR | Baseline and 6 months | Fold-change in UACR from baseline |
| Change in Creatinine Clearance | Baseline and 6 months | Fold-change in creatinine clearance by 24h urine collection (GFR-CrCl) from baseline |
Countries
United States
Participant flow
Recruitment details
This was a multicenter, phase 2, open-label study of losartan for sickle cell nephropathy. Participants were enrolled at nine centers in the United States between 2012 and 2015.
Pre-assignment details
Concomitant treatment with hydroxyurea was allowed, but the dose must have been stable in the 3 months preceding enrollment. Participants were allocated to three pre-specified groups defined by baseline urinary albumin-to-creatinine ratio (UACR).
Participants by arm
| Arm | Count |
|---|---|
| Losartan - No Albuminuria Baseline urinary albumin-to-creatinine ratio (UACR) \<30 mg/g.
All participants in this study in all arms were treated with losartan using the same dosing regimen. Study arms are only differentiated by baseline UACR. | 14 |
| Losartan - Microalbuminuria Baseline urinary albumin-to-creatinine ratio (UACR) 30-300 mg/g.
All participants in this study in all arms were treated with losartan using the same dosing regimen. Study arms are only differentiated by baseline UACR. | 12 |
| Losartan - Macroalbuminuria Baseline urinary albumin-to-creatinine ratio (UACR) \>300 mg/g.
All participants in this study in all arms were treated with losartan using the same dosing regimen. Study arms are only differentiated by baseline UACR. | 6 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Losartan - No Albuminuria | Losartan - Microalbuminuria | Losartan - Macroalbuminuria | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 4 Participants | 1 Participants | 14 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 8 Participants | 5 Participants | 18 Participants |
| Age, Continuous | 14.6 years STANDARD_DEVIATION 4.9 | 28.6 years STANDARD_DEVIATION 16.6 | 38.8 years STANDARD_DEVIATION 18.5 | 24.4 years STANDARD_DEVIATION 88.8 |
| Creatinine clearance by 24h Urine Collection | 146 mL/min/1.73m^2 STANDARD_DEVIATION 228 | 172 mL/min/1.73m^2 STANDARD_DEVIATION 204 | 108 mL/min/1.73m^2 STANDARD_DEVIATION 46.5 | 150 mL/min/1.73m^2 STANDARD_DEVIATION 56.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 12 Participants | 6 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 12 Participants | 6 Participants | 32 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 14 participants | 12 participants | 6 participants | 32 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 2 Participants | 14 Participants |
| Urinary albumin-to-creatinine ratio (UACR) (mg/g) | 8.5 mg/g STANDARD_DEVIATION 4.9 | 121 mg/g STANDARD_DEVIATION 86.6 | 815 mg/g STANDARD_DEVIATION 335.6 | 202 mg/g STANDARD_DEVIATION 333.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 12 | 0 / 6 |
| other Total, other adverse events | 0 / 14 | 1 / 12 | 0 / 6 |
| serious Total, serious adverse events | 0 / 14 | 0 / 12 | 0 / 6 |
Outcome results
Primary
Categorical Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline
Number of participants who have a ≥25% reduction in urinary albumin-to-creatinine ratio (UACR) from baseline to 6 months. This is a categorical outcome (yes/no). We hypothesized and pre-specified that ≥30% of the subjects in the microalbuminuria group would meet this outcome.
Time frame: Baseline and 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Losartan - No Albuminuria | Categorical Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline | 1 Participants |
| Losartan - Microalbuminuria | Categorical Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline | 7 Participants |
| Losartan - Macroalbuminuria | Categorical Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline | 5 Participants |
Secondary
Change in Creatinine Clearance
Fold-change in creatinine clearance by 24h urine collection (GFR-CrCl) from baseline
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Losartan - No Albuminuria | Change in Creatinine Clearance | 0.06 Fold-change |
| Losartan - Microalbuminuria | Change in Creatinine Clearance | 0.12 Fold-change |
| Losartan - Macroalbuminuria | Change in Creatinine Clearance | 0.05 Fold-change |
Secondary
Change in UACR
Fold-change in UACR from baseline
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Losartan - No Albuminuria | Change in UACR | 0.08 Fold-change |
| Losartan - Microalbuminuria | Change in UACR | -0.46 Fold-change |
| Losartan - Macroalbuminuria | Change in UACR | -0.74 Fold-change |