Preventing Sickle Cell Kidney Disease

NCT ID: NCT02373241

Last Updated: 2024-04-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-30
• Study Completion Date: 2021-07-31

Brief Summary

Untreated hypertension and renal injury are risk factors for increased morbidity and mortality in sickle cell disease, yet early markers of progressive disease have not been identified and therapies to prevent the development of adverse cardiovascular outcomes have not been defined. Circadian blood pressure, as defined by 24 hour blood pressure monitoring, is more accurate than clinic blood pressure in defining secondary hypertension and abnormal nocturnal blood pressured dipping and nocturnal hypertension have been linked to progressive renal disease in other diseases.

Methodology/Aims: A randomized feasibility trial of losartan will be conducted among adolescent HbSS and SB0 thalassemia patients (11-19 years) with abnormal nocturnal blood pressure dipping. During this six month feasibility trial, two dosing strategies of losartan (titrated to keep clinic BP <95th percentile vs. <75th percentile) will be analyzed for safety and effect on restoring normal circadian blood pressure.

A prospective cohort study among HbSS and SB0 thalassemia patients (6-19 years) will also be conducted to evaluate the incidence of hypertension and role of monitoring potential biomarkers of kidney injury and hypertension. Cohort participants will undergo annual evaluations of hypertension(24 hour blood pressure monitoring for participants ≥ 11yrs, clinic BP in all participants) and markers of kidney injury/hypertension.

Expected Results: At the completion of the feasibility trial, vital background information will be obtained to design a definitive multicenter trial of hypertension in sickle cell disease. At the completion of the cohort study, the incidence of pediatric hypertension will be identified and the role for monitoring blood and urine biomarkers will be better understood.

As therapy for patients with renal failure is dismal, it is imperative that SCD patients at risk are identified early and that therapeutic trials are conducted that prevent progression.

Detailed Description

Feasibility Trial of Losartan to Correct Abnormal Circadian Blood Pressure. Cohort participants (below) identified with in-clinic hypertension and abnormal nocturnal dipping on 24 hour ABPM will be asked to participate in a feasibility trial of losartan. Participants will be offered a consultation with Pediatric Nephrology prior to study enrollment. Participants that consent /assent will undergo repeat 24 hour ABPM to confirm abnormal circadian blood pressure prior to receiving losartan. At baseline, participants will undergo evaluation for biomarkers of kidney injury and hypertension. Participants will start on losartan at 25mg of losartan and randomized to titrate clinic BP <95th or 75th percentile based on NHLBI BP tables. Participants will be followed monthly x 6 months and receive standard of care labs. ABPM and blood/urine biomarkers of kidney injury, buccal swab for circadian genes, and hypertension will be repeated at 3 and 6 months. Participants will undergo monthly evaluation for adherence through pill counting and questionnaires. Safety of dosing will be monitored by internal review and external review (DSMB).

Prospective Pediatric Cohort to Evaluate Hypertension and Kidney Injury. Patients with HbSS or SB0 thalassemia, ages ≥ 6 years and have signed informed consent will undergo clinic BP, annual ABPM and biomarkers to determine the incidence of HTN and potential role for biomarkers as monitors for the development of hypertension or kidney injury/disease. Urine will be collected annually and evaluated for current known biomarkers of kidney disease and stored for future analysis of relevant biomarkers. Uric acid will be processed from collected blood annually.

Conditions

Anemia, Sickle Cell; Sickle Cell Disease; Kidney Disease; Hypertension; Proteinuria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard Blood Pressure Management

Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to \<95th percentile

Group Type: ACTIVE_COMPARATOR

Losartan

Intervention Type: DRUG

Standard dosing

Experimental Blood Pressure Management

Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to \<75th percentile

Group Type: EXPERIMENTAL

Losartan

Intervention Type: DRUG

Experimental dosing

Interventions

Losartan

Standard dosing

Intervention Type: DRUG

Losartan

Experimental dosing

Intervention Type: DRUG

Other Intervention Names

coozar; coozar

Eligibility Criteria

Inclusion Criteria

• Pts with HbSS or SB0 thalassemia
• Hypertension from clinic BP readings (defined by NHLBI BP tables)
• Abnormal nocturnal dipping (systolic or diastolic) as defined by <10% dip or abnormal nocturnal BP load (>25% of sleep BP readings >95th percentile as defined by AHA ABPM guidelines)
• Signed Informed Consent

Exclusion Criteria

• Patient already on BP lowering medication
• Hyperkalemia
• Pregnancy

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Jeffrey D. Lebensburger, DO

Assistant Professor of Pediatric Hematology Oncology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jeffrey D Lebensburger, DO, MSPH

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Countries

United States

References

Samuels J, Ng D, Flynn JT, Mitsnefes M, Poffenbarger T, Warady BA, Furth S; Chronic Kidney Disease in Children Study Group. Ambulatory blood pressure patterns in children with chronic kidney disease. Hypertension. 2012 Jul;60(1):43-50. doi: 10.1161/HYPERTENSIONAHA.111.189266. Epub 2012 May 14.

Reference Type: BACKGROUND

PMID: 22585950 (View on PubMed)

Seeman T, Palyzova D, Dusek J, Janda J. Reduced nocturnal blood pressure dip and sustained nighttime hypertension are specific markers of secondary hypertension. J Pediatr. 2005 Sep;147(3):366-71. doi: 10.1016/j.jpeds.2005.04.042.

Reference Type: BACKGROUND

PMID: 16182677 (View on PubMed)

Okuguchi T, Osanai T, Fujiwara N, Kato T, Metoki N, Konta Y, Okumura K. Effect of losartan on nocturnal blood pressure in patients with stroke: comparison with angiotensin converting enzyme inhibitor. Am J Hypertens. 2002 Nov;15(11):998-1002. doi: 10.1016/s0895-7061(02)02998-9.

Reference Type: BACKGROUND

PMID: 12441222 (View on PubMed)

Flynn JT, Daniels SR, Hayman LL, Maahs DM, McCrindle BW, Mitsnefes M, Zachariah JP, Urbina EM; American Heart Association Atherosclerosis, Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Update: ambulatory blood pressure monitoring in children and adolescents: a scientific statement from the American Heart Association. Hypertension. 2014 May;63(5):1116-35. doi: 10.1161/HYP.0000000000000007. Epub 2014 Mar 3. No abstract available.

Reference Type: BACKGROUND

PMID: 24591341 (View on PubMed)

Lebensburger JD, Palabindela P, Howard TH, Feig DI, Aban I, Askenazi DJ. Prevalence of acute kidney injury during pediatric admissions for acute chest syndrome. Pediatr Nephrol. 2016 Aug;31(8):1363-8. doi: 10.1007/s00467-016-3370-0. Epub 2016 Mar 24.

Reference Type: BACKGROUND

PMID: 27011218 (View on PubMed)

Aban I, Baddam S, Hilliard LM, Howard TH, Feig DI, Lebensburger JD. Severe anemia early in life as a risk factor for sickle-cell kidney disease. Blood. 2017 Jan 19;129(3):385-387. doi: 10.1182/blood-2016-09-738104. Epub 2016 Dec 5. No abstract available.

Reference Type: BACKGROUND

PMID: 27919909 (View on PubMed)

Baddam S, Aban I, Hilliard L, Howard T, Askenazi D, Lebensburger JD. Acute kidney injury during a pediatric sickle cell vaso-occlusive pain crisis. Pediatr Nephrol. 2017 Aug;32(8):1451-1456. doi: 10.1007/s00467-017-3623-6. Epub 2017 Feb 25.

Reference Type: BACKGROUND

PMID: 28238158 (View on PubMed)

Lebensburger JD, Cutter GR, Howard TH, Muntner P, Feig DI. Evaluating risk factors for chronic kidney disease in pediatric patients with sickle cell anemia. Pediatr Nephrol. 2017 Sep;32(9):1565-1573. doi: 10.1007/s00467-017-3658-8. Epub 2017 Apr 5.

Reference Type: BACKGROUND

PMID: 28382567 (View on PubMed)

Lebensburger JD, Aban I, Hilliard LM, Feig DI. Hyperuricemia and abnormal nocturnal dipping impact glomerular filtration rate in patients with sickle cell anemia. Am J Hematol. 2021 May 1;96(5):E143-E146. doi: 10.1002/ajh.26115. Epub 2021 Feb 18. No abstract available.

Reference Type: BACKGROUND

PMID: 33524174 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1K23HL127100-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

F141107009

Identifier Type: -

Identifier Source: org_study_id