Losartan to Reverse Sickle Nephropathy

A Phase II Trial of Losartan to Reverse Sickle Nephropathy

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Anemia; Nephropathy
• Intervention / Treatment: Drug: Losartan

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Kentucky
    • Louisville, Kentucky, United States, 40201
      • University of Louisville
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • NHLBI
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cincinnati, Ohio, United States, 45229
      • University of Cincinnati
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sickle cell disease; 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.	Drug: Losartan; Form: suspension, tablet. Dosage & frequency: age 6-16 = 0.7mg/kg once daily; age >16 = 50mg once daily. Duration: 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in UACR	Fold-change in UACR from baseline	Baseline and 6 months
Change in Creatinine Clearance	Fold-change in creatinine clearance by 24h urine collection (GFR-CrCl) from baseline	Baseline and 6 months

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Punam Malik, M.D., Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Quinn CT, Saraf SL, Gordeuk VR, Fitzhugh CD, Creary SE, Bodas P, George A, Raj AB, Nero AC, Terrell CE, McCord L, Lane A, Ackerman HC, Yang Y, Niss O, Taylor MD, Devarajan P, Malik P. Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial. Am J Hematol. 2017 Sep;92(9):E520-E528. doi: 10.1002/ajh.24810. Epub 2017 Jul 19.

Helpful Links

• Journal Site

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: November 16, 2011
• First Submitted That Met QC Criteria: November 22, 2011
• First Posted (Estimate): November 24, 2011

Study Record Updates

• Last Update Posted (Actual): September 29, 2020
• Last Update Submitted That Met QC Criteria: September 28, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Kidney Diseases; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: 2010-3070

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No