Preventing Sickle Cell Kidney Disease

Study Overview
=================
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.

Official Title
-----------------
Chronobiology and Chronopharmacology to Prevent Sickle Cell Kidney Disease

Conditions
-----------------
Anemia, Sickle Cell, Sickle Cell Disease, Kidney Disease, Hypertension, Proteinuria

Intervention / Treatment
-----------------
* Drug: Losartan
* Drug: Losartan


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 25 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Blood Pressure Management<br>Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <95th percentile | Drug: Losartan<br>* Standard dosing<br>* Other names: coozar;|
| Experimental: Experimental Blood Pressure Management<br>Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <75th percentile | Drug: Losartan<br>* Experimental dosing<br>* Other names: coozar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility as Measured by the Number of Patients That Accept Enrollment, Remain Adherent to Losartan, and Remain Adherent to Study Procedures. | Outcome 1a. Document the rate of acceptance (quantitative) and reasons for acceptance/rejection (qualitative) in a randomized trial of trial of losartan for SCD patients with abnormal nocturnal blood pressures. Outcome 1b. Identify the adherence rate to losartan during a randomized three year trial of losartan for SCD patients (n=40) with abnormal nocturnal blood pressure. Outcome 1c. Determine the adherence rate to study procedures among participants enrolled in a three year trial of losartan for SCD patients (n=40) with abnormal nocturnal blood pressure. | 5 yrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Incident Hypertension | We will prospectively evaluate the incidence of hypertension (Clinic BP in pts >5yrs and ABPM in pts >10 yrs) and role of blood and urine biomarkers (pts >5ys) among participants with HbSS or SB0 thalassemia (expected cohort n=200) over 5 yrs. We identified 20 participants (34%) with incident hypertension but randomized one to the study. The study was terminated as the eGFR was determined not to be a reliable endpoint in pediatric sickle cell. | 5 yrs | 
| Feasibility as Measured by the Number of Patients With Improvement in Nocturnal Blood Pressure While Receiving Losartan. | As a feasibility trial, the effect of losartan on lowering nocturnal hypertension will be monitored to identify the difference in nocturnal BP improvement between the two treatment arms, and within group standard deviation of BP | 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Anemia, Sickle Cell, Sickle Cell Disease, Kidney Disease, Hypertension, Proteinuria, Losartan, Antihypertensive Agents, Blood Pressure