Preventing Sickle Cell Kidney Disease

Sponsor
University of Alabama at Birmingham (Other)
Overall Status
Terminated
CT.gov ID
NCT02373241
Collaborator
National Heart, Lung, and Blood Institute (NHLBI) (NIH)
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Study Details

Study Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
1 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Chronobiology and Chronopharmacology to Prevent Sickle Cell Kidney Disease
Study Start Date :
Apr 1, 2015
Actual Primary Completion Date :
Feb 1, 2021
Actual Study Completion Date :
Jul 1, 2021

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Standard Blood Pressure Management

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

Drug: Losartan
Standard dosing
Other Names:
  • coozar
  • Experimental: Experimental Blood Pressure Management

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

    Drug: Losartan
    Experimental dosing
    Other Names:
  • coozar
  • Outcome Measures

    Primary Outcome Measures

    1. Feasibility as Measured by the Number of Patients That Accept Enrollment, Remain Adherent to Losartan, and Remain Adherent to Study Procedures. [5 yrs]

      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.

    Secondary Outcome Measures

    1. Number of Patients With Incident Hypertension [5 yrs]

      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.

    2. Feasibility as Measured by the Number of Patients With Improvement in Nocturnal Blood Pressure While Receiving Losartan. [5 years]

      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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    5 Years to 25 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama at Birmingham Birmingham Alabama United States 35223

    Sponsors and Collaborators

    • University of Alabama at Birmingham
    • National Heart, Lung, and Blood Institute (NHLBI)

    Investigators

    • Principal Investigator: Jeffrey D Lebensburger, DO, MSPH, University of Alabama at Birmingham

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Jeffrey D. Lebensburger, DO, Assistant Professor of Pediatric Hematology Oncology, University of Alabama at Birmingham
    ClinicalTrials.gov Identifier:
    NCT02373241
    Other Study ID Numbers:
    • F141107009
    • 1K23HL127100-01
    First Posted:
    Feb 26, 2015
    Last Update Posted:
    May 9, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Keywords provided by Jeffrey D. Lebensburger, DO, Assistant Professor of Pediatric Hematology Oncology, University of Alabama at Birmingham
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Standard Blood Pressure Management Experimental Blood Pressure Management
    Arm/Group Description Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <95th percentile Losartan: Standard dosing Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <75th percentile Losartan: Experimental dosing
    Period Title: Overall Study
    STARTED 0 1
    COMPLETED 0 1
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Standard Blood Pressure Management Experimental Blood Pressure Management Total
    Arm/Group Description Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <95th percentile Losartan: Standard dosing Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <75th percentile Losartan: Experimental dosing Total of all reporting groups
    Overall Participants 0 1 1
    Age (Count of Participants)
    <=18 years
    1
    Infinity
    1
    100%
    Between 18 and 65 years
    0
    NaN
    0
    0%
    >=65 years
    0
    NaN
    0
    0%
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    16
    16
    Sex: Female, Male (Count of Participants)
    Female
    0
    NaN
    0
    0%
    Male
    1
    Infinity
    1
    100%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    NaN
    0
    0%
    Asian
    0
    NaN
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    NaN
    0
    0%
    Black or African American
    1
    Infinity
    1
    100%
    White
    0
    NaN
    0
    0%
    More than one race
    0
    NaN
    0
    0%
    Unknown or Not Reported
    0
    NaN
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    1
    Infinity
    1
    100%

    Outcome Measures

    1. Primary Outcome
    Title Feasibility as Measured by the Number of Patients That Accept Enrollment, Remain Adherent to Losartan, and Remain Adherent to Study Procedures.
    Description 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.
    Time Frame 5 yrs

    Outcome Measure Data

    Analysis Population Description
    We stopped the RCT as eGFR was determined not to be an accurate measure of GFR in SCD patients
    Arm/Group Title Standard Blood Pressure Management Experimental Blood Pressure Management
    Arm/Group Description Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <95th percentile Losartan: Standard dosing Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <75th percentile Losartan: Experimental dosing
    Measure Participants 0 1
    Count of Participants [Participants]
    0
    NaN
    1
    100%
    2. Secondary Outcome
    Title Number of Patients With Incident Hypertension
    Description 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.
    Time Frame 5 yrs

    Outcome Measure Data

    Analysis Population Description
    This study was terminated early so we did not perform analysis of losartan on incident hypertension.
    Arm/Group Title Standard Blood Pressure Management Experimental Blood Pressure Management
    Arm/Group Description Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <95th percentile Losartan: Standard dosing Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <75th percentile Losartan: Experimental dosing
    Measure Participants 0 1
    Count of Participants [Participants]
    0
    NaN
    1
    100%
    3. Secondary Outcome
    Title Feasibility as Measured by the Number of Patients With Improvement in Nocturnal Blood Pressure While Receiving Losartan.
    Description 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
    Time Frame 5 years

    Outcome Measure Data

    Analysis Population Description
    We did not have any patients randomized to standard blood pressure management
    Arm/Group Title Standard Blood Pressure Management Experimental Blood Pressure Management
    Arm/Group Description Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <95th percentile Losartan: Standard dosing Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <75th percentile Losartan: Experimental dosing
    Measure Participants 0 1
    Count of Participants [Participants]
    1
    Infinity

    Adverse Events

    Time Frame 5 years
    Adverse Event Reporting Description No adverse events reported
    Arm/Group Title Standard Blood Pressure Management Experimental Blood Pressure Management
    Arm/Group Description Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <95th percentile Losartan: Standard dosing Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to <75th percentile Losartan: Experimental dosing
    All Cause Mortality
    Standard Blood Pressure Management Experimental Blood Pressure Management
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/0 (NaN) 0/1 (0%)
    Serious Adverse Events
    Standard Blood Pressure Management Experimental Blood Pressure Management
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/0 (NaN) 0/1 (0%)
    Other (Not Including Serious) Adverse Events
    Standard Blood Pressure Management Experimental Blood Pressure Management
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/0 (NaN) 0/1 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT 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.

    Results Point of Contact

    Name/Title Jeffrey Lebensbugrer
    Organization University of Alabama at Birmingham
    Phone 2056389285
    Email jlebensburger@uabmc.edu
    Responsible Party:
    Jeffrey D. Lebensburger, DO, Assistant Professor of Pediatric Hematology Oncology, University of Alabama at Birmingham
    ClinicalTrials.gov Identifier:
    NCT02373241
    Other Study ID Numbers:
    • F141107009
    • 1K23HL127100-01
    First Posted:
    Feb 26, 2015
    Last Update Posted:
    May 9, 2022
    Last Verified:
    May 1, 2022