Losartan to Reverse Sickle Nephropathy

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Completed
• CT.gov ID: NCT01479439
• Collaborator: (none)
• Enrollment: 36
• Locations: 9
• Arm: 1
• Duration (Months): 46
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Nephropathy; Sickle Cell Anemia	Drug: Losartan	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Losartan to Reverse Sickle Nephropathy
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Change in UACR [Baseline and 6 months]

   Fold-change in UACR from baseline

2. Change in Creatinine Clearance [Baseline and 6 months]

   Fold-change in creatinine clearance by 24h urine collection (GFR-CrCl) from baseline

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

1. 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.

2. Subjects with child-bearing potential must be willing to use a medically accepted form of contraception throughout the study.

3. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois at Chicago	Chicago	Illinois	United States	60612
2	University of Louisville	Louisville	Kentucky	United States	40201
3	NHLBI	Bethesda	Maryland	United States	20892
4	Akron Children's Hospital	Akron	Ohio	United States	44308
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
6	University of Cincinnati	Cincinnati	Ohio	United States	45229
7	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
8	University of Texas Southwestern	Dallas	Texas	United States	75390
9	Texas Children's Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Journal Site

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT01479439
• Other Study ID Numbers: 2010-3070
• First Posted: Nov 24, 2011
• Last Update Posted: Sep 29, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Kidney Diseases; Anemia, Sickle Cell; Losartan

Study Results

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 Detail	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).

Arm/Group Title	Losartan - No Albuminuria	Losartan - Microalbuminuria	Losartan - Macroalbuminuria
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	15	13	8
COMPLETED	14	12	6
NOT COMPLETED	1	1	2

Baseline Characteristics

Arm/Group Title	Losartan - No Albuminuria	Losartan - Microalbuminuria	Losartan - Macroalbuminuria	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	14	12	6	32
Age (Count of Participants)
<=18 years	9 64.3%	4 33.3%	1 16.7%	14 43.8%
Between 18 and 65 years	5 35.7%	8 66.7%	5 83.3%	18 56.3%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.6 (4.9)	28.6 (16.6)	38.8 (18.5)	24.4 (88.8)
Sex: Female, Male (Count of Participants)
Female	6 42.9%	8 66.7%	4 66.7%	18 56.3%
Male	8 57.1%	4 33.3%	2 33.3%	14 43.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	14 100%	12 100%	6 100%	32 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	14 100%	12 100%	6 100%	32 100%
White	0 0%	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	12 100%	6 100%	32 100%
Urinary albumin-to-creatinine ratio (UACR) (mg/g) (mg/g) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/g]	8.5 (4.9)	121 (86.6)	815 (335.6)	202 (333.8)
Creatinine clearance by 24h Urine Collection (mL/min/1.73m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73m^2]	146 (228)	172 (204)	108 (46.5)	150 (56.5)

Outcome Measures

1. Primary Outcome

Title	Categorical Change in Urinary Albumin-to-creatinine Ratio (UACR) From Baseline
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Losartan - No Albuminuria	Losartan - Microalbuminuria	Losartan - Macroalbuminuria
Arm/Group Description	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.	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.	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.
Measure Participants	14	12	6
Count of Participants [Participants]	1 7.1%	7 58.3%	5 83.3%

2. Secondary Outcome

Title	Change in UACR
Description	Fold-change in UACR from baseline
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	No Albuminuria (NoA)	Microalbuminuria (MicroA)	Macroalbuminuria
Arm/Group Description	Baseline urinary albumin-to-creatinine ratio (UACR) <30 mg/g	Baseline urinary albumin-to-creatinine ratio (UACR) 30-300 mg/g	Baseline urinary albumin-to-creatinine ratio (UACR) >300 mg/g
Measure Participants	14	12	6
Median (Inter-Quartile Range) [Fold-change]	0.08	-0.46	-0.74

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	No Albuminuria (NoA)	Microalbuminuria (MicroA)	Macroalbuminuria
Arm/Group Description	Baseline urinary albumin-to-creatinine ratio (UACR) <30 mg/g	Baseline urinary albumin-to-creatinine ratio (UACR) 30-300 mg/g	Baseline urinary albumin-to-creatinine ratio (UACR) >300 mg/g
Measure Participants	14	12	6
Median (Inter-Quartile Range) [Fold-change]	0.06	0.12	0.05

Adverse Events

Arm/Group Title	No Albuminuria (NoA)		Microalbuminuria (MicroA)		Macroalbuminuria
Arm/Group Description	Baseline urinary albumin-to-creatinine ratio (UACR) <30 mg/g		Baseline urinary albumin-to-creatinine ratio (UACR) 30-300 mg/g		Baseline urinary albumin-to-creatinine ratio (UACR) >300 mg/g
All Cause Mortality
	No Albuminuria (NoA)		Microalbuminuria (MicroA)		Macroalbuminuria
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/12 (0%)		0/6 (0%)
Serious Adverse Events
	No Albuminuria (NoA)		Microalbuminuria (MicroA)		Macroalbuminuria
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/12 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	No Albuminuria (NoA)		Microalbuminuria (MicroA)		Macroalbuminuria
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		1/12 (8.3%)		0/6 (0%)
Musculoskeletal and connective tissue disorders
Muscle Cramps	0/14 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0
Renal and urinary disorders
Increase in serum creatinine >50% from baseline	0/14 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0
Decline in GFR >25% from baseline	0/14 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0

Limitations/Caveats

We cannot conclude from this small phase 2 study that losartan is efficacious for sickle cell nephropathy. Rather, the data generated from this study will inform the design of a phase-3 randomized trial to determine its efficacy.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.