Clinical trial NCT02373241
Conditions: Anemia, Sickle Cell Sickle Cell Disease Kidney Disease Hypertension Proteinuria
Keywords: Anemia, Sickle Cell Sickle Cell Disease Kidney Disease Hypertension Proteinuria Losartan Antihypertensive Agents Blood Pressure
Sponsor: University of Alabama at Birmingham
Start date: 2015-04-01; Completion date: 2021-07-01
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to \<95th percentile arm 2: Participants initiated on 25mg of losartan daily and randomized to lower in-clinic BP to \<75th percentile
Interventions: intervention 1: Losartan intervention 2: Losartan
Intervention descriptions: intervention 1: Standard dosing intervention 2: Experimental dosing

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 34 
Version Date: 11/26/18 
Chronobiology and Chronopharmacology to Prevent 
Sickle Cell Nephropathy Feasibility Trial 
 
 
Study Protocol & Statistical Analysis Plan 
 
NCT02373241 
 
 
Version 1.1 11/26/2018 
 
 
Jeffrey Lebensburger, DO, MSPH, Principal Investigator 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 
 
 


Page 2 of 34 
Version Date: 11/26/18 
 
INTRODUCTION AND OBJECTIVES 
Chronic Kidney Disease and End Stage Renal Disease in Sickle Cell Disease 
In adults with sickle cell disease (SCD), ~ 40% of patients have chronic kidney disease 
which may be associated with hypertension and albuminuria.[1]  In this SCD patient 
population, 12% of patients progress to renal failure and 15-30% of deaths in SCD are 
related to kidney disease.[2,3]  The treatment for a patient that has renal failure is 
dialysis, often as a bridge to renal transplantation.  Dialysis records suggest that 0.1-
0.5% of those patients initiated on dialysis for end stage renal disease (ESRD) have 
SCD and these patients were are nearly 7 years younger than the average dialysis at 
the time of initiation.[4-6]  The one year mortality rate for dialysis patients with SCD may 
be three times higher than patients with ESRD but without SCD and the mean survival 
time after initiating dialysis is only 4 years.[6,7]  Renal transplantation is a viable option 
for sickle cell patients on dialysis and may improve survival.[4,5,8] However, this patient 
population is less likely to be offered or receive renal transplantation which may be due 
in part to lower survival of grafts or patients with SCD as compared to other diseases 
with ESRD. [8,9]   The known progression to and poor survival of SCD patients with 
chronic kidney disease mandates early identification of patients at risk and therapies 
that may prevent progression.   
Sickle Cell Disease and Potential Biomarkers of Chronic Kidney Disease 
Toddlers with SCD may initially develop hyperfiltration which progressively declines during 
adolescence and young adulthood and indicates progression to chronic kidney disease.[10,11]  
A cross-sectional study of adolescent SCD patients identified in-clinic systolic BP as a risk for 
worsening glomerular filtration rate.[12]  Pediatric patients with sickle cell disease also 
develop microalbuminuria (microalbumin/creatinine >30mcg/mg) and proteinuria 
(>300mcg/mg) which may proceed kidney disease.  Several studies have evaluated the 
presence of albuminuria pediatric sickle cell disease. (Table) 
Author 
Sample size 
Prevalence 
Correlations 
McKie[13] 
191 
37/191 (19.4%) 
Lower Hb, Age 
McBurney[14] 
142 
Overall: 19%  
7-14yrs: 18/75 (24%) 
15+: 9/31 (29%) 
Lower Hb, Age  
Gurkan[15] 
40 (33 HbSS) 
MiA- 6/40 (15%) 
MA- 2/40 (5%) 
No MiA <12yrs 
LDH and MiA (not correlated with 
HbSS alone) 
Becton[16] 
90 
 14/90 (16%) 
Lower Hb, Increasing BP 
McPherson[17] 
261 
60/261 (23%) 
Lower Hb, Age 
Egberue[18] 
69 
14/69 (20.3%) 
>9yrs: 23% 
Age 
Alvarez[19] 
165 (SS and SC) 
46/165 (28%) 40 HbSS. 
8/46 had MA 
MA vs. MiA: Lower Hb, Higher Retic, 
Lower GFR 


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Dharnidharka[20] 
102 
MiA (>20mg/g Cr) 
Overall: 26.5% 
10-18yrs:46% 
Age 
Lebensburger[21] 
144 
32/144 (22%) 
Low Hb 
Mawanda[22] 
305 
86/305 (28.2%) 
Low Hb, Age, more transfusions 
Aygun[12] 
85 
15.9% 
Blood Pressure, Low WBC and ANC 
The novel biomarkers Kim-1 and NAG are higher in SCD patients with albuminuria. 
[23,24]  Cystatin C has been negatively correlated with hemoglobin and positively 
correlated with age, B2M and NAG.[25] 
Abnormal Ambulatory Blood Pressure in Pediatrics is a Risk Factor for Chronic 
Kidney Disease:   
Hypertension, based on in-clinic BP, in SCD patients has been associated with 
albuminuria and hyperfiltration.[12,16,18,26-28]   Additional SCD studies have 
associated in-clinic hypertension as a risk factor chronic kidney disease and renal 
failure.[9,29,30]  In non-SCD pediatric populations, 24 hour ambulatory blood pressure 
is more accurate than clinic BP in defining secondary hypertension and abnormal 24 hr 
ABPM has been strongly linked to progressive renal disease.[31-35]  In the large 
pediatric study Chronic Kidney Disease in Children (CKiD), an association was 
identified between abnormal ABPM and progression of proteinuria and renal function 
decline.[36]  Despite the recent emphasis on utilizing 24 hr ABPM in clinical trials for 
other diseases, in SCD, the roles of hypertension defined by ABPM as a risk factor for 
kidney injury or intensive antihypertensive therapy to prevent the devastating 
complications of CKD has not been explored. 
Selection of Angiotensin II Antagonist Therapy to Correct Abnormal Ambulatory 
Blood Pressure. 
Despite the high prevalence of hypertension in SCD and increased morbidity and 
mortality from cardiovascular disease, there are currently no randomized clinical trials in 
SCD to demonstrate 1) the appropriate selection of an antihypertensive medication, or 2) 
dosing of that medication in the pediatric setting.  Angiotensin Converting Enzyme 
Inhibitors and Angiotensin II Antagonists both may reduce proteinuria and abnormal blood 
pressure in SCD patients.  The rationale for selecting losartan in this feasibility trial is that 
unlike ACE Inhibitors, Angiotensin II Antagonists do not accumulate bradykinin which may 
contribute to nocturnal hypertension; losartan, unlike other Angiotensin II Antagonists, 
has uricosuric effect which may be important as uric acid may be associated with 
abnormal circadian BP and uricosuric medications may lower blood pressure (Table 
4).[37-41] Of great interest, an ambulatory blood pressure clinical trial comparing an 
Angiotensin II Antagonist (Losartan) to an ACE Inhibitor (quinapril) demonstrated that 
losartan preferentially decreased nocturnal hypertension.[42]  The findings of a reduction 
in nocturnal hypertension by Angiotensin II Antagonists was replicated in additional 
studies and independent of time the drug was administered. [43,44]   
Rationale for Evaluating Safety of Using an Intensive BP Treatment Strategy 


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Current standard of care in our institution is to place pediatric patients on an 
antihypertensive medication with a goal of reducing BP to <95th percentile based on 
NHLBI BP Tables for Children and Adolescent. A recent meta-analysis of 11 trials 
identified intensive blood pressure therapy (BP<50th or 75th percentile) as compared to 
standard therapy reduced adverse outcomes, most effectively in patients with 
concomitant proteinuria. [45]  Pediatric non-SCD trials using intensive anti-hypertensive 
therapy guided by 24 hr ABPM resulted in decrease progression to CKD.[46,47]   In a 
large non-SCD pediatric randomized trial of intensive vs. standard therapy for control of 
24 hours blood pressure with an ACE Inhibitor, intensive BP control improved renal 
outcomes and the greatest impact was seen in patients with glomerulopathies.[46]  As 
most SCD patients without renal disease have low BP relative to the black population, a 
target of 95 percentile BP may be physiologically hypertensive in SCD and intensive BP 
may be more appropriate. As no prospective anti-hypertensive trials focused on 
adolescent patients with SCD, it is vital to first conduct a feasibility trial to determine the 
safety and tolerability of standard and intensive dosing strategies 
1.1  
AIMS OF THE TRIAL 
1.1.a Primary Objectives 
To identify participants at risk for developing progressive kidney disease and to target 
therapeutic approaches that prevents progressive kidney disease.  The primary 
endpoint is to conduct a randomized feasibility trial of losartan among participants with 
abnormal ambulatory blood pressure.  We expect that 30% of participants in a pediatric 
hypertension cohort (n=60) will have abnormal ambulatory blood pressure and 
abnormal clinic blood pressure.  Of these sixty participants, we estimate that 40 
participants will accept enrollment in the feasibility trial. 
1.1.b Secondary Objectives 
Objective 1: To determine the acceptability of enrollment and retention in a randomized 
feasibility trial of losartan 
Objective 2: To determine the safety of losartan at two different dosing strategies 
Objective 3: To complete the necessary preparations for a definitive phase III trial 
including preparing a manual of operations, case report forms, and sample size 
calculations 
2.0 STUDY OVERVIEW AND DESIGN 
2.1 Study Overview. 


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2.1.a Cohort Study (X130312027) already approved cohort study being conducted) 
A five year prospective cohort study will be conducted among participants with HbSS or 
SB0 thalsassemia ages 5-22 years of age.  The study will evaluate standard of care 
labs and medical history (including type of sickle cell therapy) to determine the 
incidence of hypertension and markers of progressive kidney injury.  Annually, 
participants will undergo research evaluations using 24 hour ambulatory blood pressure 
monitoring and analysis of urine samples for biomarkers of kidney injury.  Participants 
with abnormal nocturnal blood pressure dipping will be eligible for this feasibility trial. 
2.2 Randomized Feasibility Trial- 
A randomized feasibility trial of losartan for the correction of abnormal nocturnal blood 
pressure dipping in adolescent patients with HbSS or SB0 thalsassemia 11-22 years of 
age who have documented hypertensive blood pressure in clinic will be conducted.  
Participants will be randomized to losartan at doses to maintain clinic BP either <95th 
percentile (standard dosing strategy) or <75th percentile (intensive dosing strategy).   
The study will be analyzed using intention to treat for outcomes which will begin 
immediately after randomization to losartan.  Participants will be followed monthly as 
standard of care with additional research procedures of performing ambulatory blood 
pressure monitoring at baseline, 3 months, and 6 months and urine/blood biomarkers of 
kidney injury at baseline, 3 months and 6 months.  We propose to identify 60 eligible 
participants of which 40 will participate in the randomized feasibility trial.  The 
parents/legal guardians of these children will have a one hour educational session on 
hypertension and kidney disease in sickle cell disease.  The parents/legal guardians will 
be offered the opportunity to discuss hypertension and kidney disease with a Pediatric 
Nephrologist prior to participation in the trial.   
2.2.a. Eligibility for the Feasibility Trial 
Inclusion Criteria for Pediatric Cohort (Separate IRB approved study-X130312027)) 
1. Participant must have sickle cell anemia (hemoglobin SS) or sickle -
thalassemia (hemoglobin S) as confirmed at the local institution by hemoglobin 
analysis. 
2. Participant must be 5 to 22 years of age (i.e., must not have attained their 23rd  
birthday).   
3. Informed consent in accordance with the institutional policies (institutional IRB 
approval) and Federal guidelines (approved by the United States Department of 
Health and Human Services) must be signed by the participant's legally 
authorized guardian acknowledging written consent to join the study.  
 
 


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Version Date: 11/26/18 
2.2.b. Inclusion Criteria for Feasibility Trial Screening 
1. Enrolled in Pediatric Cohort Study  
2. History of abnormal clinic blood pressure (3 abnormal blood pressure readings 
(systolic or diastolic) in last 4 visits) as defined by NHLBI Blood Pressure Tables 
for age and height. 
3. History of 1) abnormal nocturnal blood pressure dipping as defined by <10% dip 
(daytime-nightime systolic or diastolic blood pressure/daytime blood pressure x 
100) or 2) abnormal nocturnal load defined by >25% sleep BP >95th percentile. 
4. Informed consent in accordance with the institutional policies (institutional IRB 
approval) and Federal guidelines (approved by the United States Department of 
Health and Human Services) must be signed by the participant's legally 
authorized guardian acknowledging written consent to join the study 
 
2.2.c. Exclusion Criteria for Feasibility Trial Screening 
1. Participant with history of angioedema to prior ARB or ACE inhibitor 
2. Participants with moderate to severe renal impairment (GFR <60mL/min/1.73m2) 
3. Co-administration of another hypertensive medication 
4. History of known bilateral renal artery stenosis, unilateral renal artery stenosis to a 
solitary kidney 
5. Hyperkalemia at time of screening (K>6 mmol/L- non-hemolyzed sample) 
6. Pregnancy 
7. Current use of lithium, digitalis, warfarin 
 
2.2.d. Inclusion Criteria for Feasibility Trial Randomization 
1. Repeat ABPM demonstrating abnormal blood pressure dipping (systolic or 
diastolic dipping <10%) or abnormal nocturnal load 
2. Complete a Survey of Barriers and Facilitators to Enrollment in a Pediatric SCD 
Hypertension Trial  
 
2.3 BASELINE EVALUATION AND FOLLOW-UP 
 
2.3.a Baseline Evaluations 
1. Screening  
a. Eligible participants will undergo repeat 24 hour ABPM to confirm 
abnormal nocturnal dipping prior to randomization.  
b. Participants, and if participants is a minor, parents/guardians, with 
abnormal 24 hour ABPM will be educated about hypertension, kidney 
disease in SCD.  Participants will also be offered consult with Pediatric 
Nephrologist prior to randomization. 
 
2. Randomization 
a. Participants will have overnight urine collected for biomarker analysis.  
Participants can be consented to allow additional urine to be stored for 
future urine studies of kidney injury. 


Page 7 of 34 
Version Date: 11/26/18 
b. Participants will have standard of care labs obtained including CBC with 
diff, CMP with LDH and uric acid, urine for microalbumin/creatinine ratio, 
Cystatin c 
c. Participants can be consented to Buccal Cell collection 
2.3.b Follow-up 
1. Monthly evaluations (6 months total from randomization) 
a. Participants will have monthly clinic visits 
b. Obtain vital signs 
c. Obtain standard of care labs: including CBC, CMP 
d. Complete assessment of potential side effects of losartan   
e. Complete assessment of adherence   
2. Three months from randomization 
a. Obtain overnight urine specimens for urine biomarkers including standard 
evaluation of  microalbumin/creatinine ratio and experimental evaluation of 
biomarkers 
b. Obtain cystatin C 
c.  Buccal Cell Collection 
d. Repeat 24 hour ABPM 
3. Six months from randomization 
a. Obtain overnight urine specimens for urine biomarkers including standard 
evaluation of  microalbumin/creatinine ratio and experimental evaluation of 
biomarkers 
b. Obtain cystatin C 
c. Buccal Cell collection 
d. Repeat 24 hour ABPM 
 
Table XX: Baseline and monthly evaluations 
Test 
Entry 1 mo 2 mo 
3 mo 
4 mo 
5 mo 
6 mo 
Vital Signs, Hx and PE 
X 
X 
X 
X 
X 
X 
X 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
Adherence Measures 
  
X 
X 
X 
X 
X 
X 
Ferritin 
X 
 
 
X 
 
 
X 
Cystatin C 
X 
 
 
X 
 
 
X 
Uric Acid 
X 
 
 
X 
 
 
X 
Urine Microalbumin/Creatinine 
X 
 
 
X 
 
 
X 
Overnight Urine Collection 
X 
 
 
X 
 
 
X 
24 hr ABPM 
X 
 
 
X 
 
 
X 
Urine and blood biomarkers 
X 
 
 
X 
 
 
X 
Pregancy Test 
X 
X 
X 
X 
X 
X 
X 
Enrollment Survey 
X 
 
 
 
 
 
 
Buccal Cell collection 
X 
 
 
X 
 
 
X 
 
 
3. UNDERSTANDING ENROLLMENT  


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All participants approached to participate in the feasibility trial have consented to the 
cohort study, but will be asked to complete a survey to identify barriers/facilitators to 
enrollment in a drug trial.  Quantitative surveys questions will include Likert questions to 
determine barriers/facilitators to participation in this trial using two direction intensity 
scale (strongly agree, agree, disagree, and strongly disagree.  The questionnaire will be 
piloted among adolescent SCD patients not eligible for the feasibility trial.   
 
4. BLOOD PRESSURE MONITORING 
 
4.1. 
CLINIC BLOOD PRESSURE MONITORING 
Participants will have standard of care blood pressure monitoring in clinic.  
Participants will have blood pressure obtained in a sitting position. Blood pressure 
cuffs will be selected by study member or clinic nurse and applied to the participant’s 
non-dominant arm.  The cuff bladder should cover at least two thirds of the upper 
arm and the bladder should encircle 80% to 100% of the circumference of the arm.  
Blood pressure should be measured twice in a controlled environment after 3-5 
minutes of sitting.   
 
4.2. 
AMBULATORY BLOOD PRESSURE MONITORING 
SpaceLabs 90217 monitors will be used to perform 24 hour ABPM.  Participants and 
parents/guardians will be educated on how to operate the monitor including how to 
stop a reading if there is excessive discomfort, what to expect when a reading is 
obtained, and need to keep the arm still during BP readings.  Participants will be 
educated that BP will be recorded every 20 minutes during the day and every 30 
minutes from 10PM to 6 AM.  If the monitor is removed, the device should be 
removed immediately after a recording and reapplied as soon as possible.  
Participants should immediately contact the study team if apparent allergic reaction 
or extreme uncomfortable pressure.  Finally, participants will be educated to keep a 
log book of activity during the day including activities that may influence BP.  At 
minimum, the log should record sleep and wake times. 
 
Blood pressure cuffs will be selected by study member and applied to the 
participant’s non-dominant arm.  The cuff bladder should cover at least two thirds of 
the upper arm and the bladder should encircle 80% to 100% of the circumference of 
the arm.  The study member will allow the ABPM to inflate two times prior to leaving 
the clinic. Participants will receive a pre-addressed stamped FedEx box to return the 
diary and monitor to study team.  Participants who do not complete ABPM will 
participate in an interview to determine the barriers to completing the ABPM and 
facilitators that would enhance adherence.   
 
4.3. 
ABPM INTERPRETATION 
To be considered an acceptable procedure, the following readings must be 
recorded: 1) A minimum of 1 reading per hour including during sleep and 2) total of 
40 readings during the period.   
      Values outside the following range will be discarded 
1) SBP 60-220 mm Hg 


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2) DBP 35-120 mm Hg 
3) Heart rate: 40-180 BPM 
4) Pulse pressure 40-120 mm Hg 
The following calculations will be recorded 
1) Mean Ambulatory SBP and DBP for the entire 24 hour period, awake period, and 
sleep period 
2) Dipping will be calculated as ((Mean Awake BP- Mean Sleep BP)/Mean Awake 
BP) x 100.  Normal Dipping will be defined as >10% dipping.  Reverse Dipping 
will be defined as mean sleep BP that is higher than mean Awake BP. 
3) BP Load is the percentage of systolic and diastolic BP readings above the 95th 
percentile for the 24 hour, awake, and sleep periods as defined by the 2014 
Statement from the  American Heart Association- Update: Ambulatory Blood 
Pressure Monitoring in Children and Adolescents. 
4) BP index will be calculated as the mean BP/normative data for 95th BP for the 24 
hour, awake, and sleep periods. 
5.1. URINE BIOMARKERS 
Urine will be collected by the patient on any urine overnight and first urine in the 
morning into a sterile container provided by the study coordinator.  Urine will be 
collected at 0, 3, and 6 months.   The urine will be centrifuged and aliquoted into 
10 microcontainers within one hour.  Five microcontainers will be sent 
immediately to the UAB lab of Dr. Jennifer Pollock and David Pollock.  Five 
microcontainers will be stored at -80 degrees Celsius at the Children’s of 
Alabama Lab. Two of the frozen microcontainers from each participant will be 
sent to the UAB-UCSD O’Brien Center for Acute Kidney Injury Research, 
Bioanalytical Core at 3-6 month by Fed Ex Overnight shipping on dry ice to 
UCSD on Mon or Tues (once every 3 months).  Dr. Satish Rao at UCSD will 
analyze urine for Kidney Injury Marker-1 (KIM-1), Neutrophil gelatinase-
associated lipocalin (NGAL), and Beta-2-microglobulin.  One urine sample 
microcontainer tube per patient will be sent to Dr. John Moore’s lab at UAB to be 
analyzed for cystatin-C, urine albumin/creatinine. 
5.2. ADDRESSING NOVEL BIOMARKERS 
Participants can consent to use of urine for future evaluations of kidney disease 
or hypertension.  Two remaining microcontainers will be kept in a research 
freezer.  During the course of the study, the principal investigator may be able to 
analyze the urine samples for novel biomarkers of hypertension or kidney injury. 


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5.3 BLOOD BIOMARKERS 
 Uric acid will be processed and analyzed by Children’s of Alabama laboratory.  10mL of 
whole blood will be collected in EDTA tubes and sent to the UAB laboratory of Drs. 
Jennifer and David Pollock for analysis to include: thiobarbituric acid reactive 
substances, endothelin, aldosterone, BNP, and renin. 
5.4. BUCCAL CELL SWABS 
Participants will have buccal cell swab testing performed at three times during the study 
(entry, 3 mo, and 6mo).  The goal of the buccal swab testing is to determine if abnormal 
nocturnal blood pressure in sickle cell disease is related to abnormal circadian rhythms.  
In animal models, an abnormal circadian rhythm is associated with hypertension.  The 
swabs will be collected at multiple time points (6AM, 10AM, 6PM, 10PM) to determine 
the circadian rhythms in this patient population.   
Participants will be given 3 bags: one with buccal swabs, one with labeled tubes, and an 
empty bag to place the tubes containing the swab tips after each collection.  Holding the 
handle end of the swab, participants will scrape the swab collection tip firmly against the 
inside of the cheek 6 times (about 10 seconds).  After taking the sample, the participant 
will eject the tip by pushing down the plunger at the end of the handle into the tube 
labelled for that time.  Ensure the lid on the tube is tight.  Place the tube into a bag and 
refrigerate the bag. 
 
6. LOSARTAN DOSING AND MONITORING 
Prior to randomization, participants will need to have 1) three documented blood 
pressure recordings (in last 4 visits) documenting a systolic or diastolic blood pressure 
that is >95th percentile for age, gender, and height as defined by NHBLI BP tables and 
2) two 24 hour ABPM recordings documenting abnormal nocturnal blood pressure 
dipping.  
6.1.Initial Dose:  All participants will be initiated on 25 mg of losartan at their initial 
monthly visit.   
6.2.Randomization scheme.  
This trial will use block randomization with 6 participants per block. The blocks will be 
put in sealed envelopes and seven blocks out of 10 possible blocks will be selected by 
the pharmacist.  Participants assigned A will receive intensive dosing of losartan (titrate 


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to keep BP <75th percentile) and B will receive standard dosing of losartan (titrate to 
keep BP <95th percentile). 
6.3. Losartan dosing 
Participants will have their dose increased by the study team based on blood pressure 
response at monthly clinic visits to a max of 1.4mg/kg/day or 100mg/day.  Dosing will be 
rounded to the closest 25 mg tablet.  The study coordinator and PI will review the mean 
BP obtained by aneroid technique during the clinic visit and compared to either the 75th 
or 95th percentile normative data for systolic and diastolic BP by age, height, and 
gender.  A dose can be increased for either a systolic or diastolic BP that is greater than 
the randomized target BP goal).  Participants that miss a dose should not take an extra 
dose, rather the participant should resume their usual schedule.  Losartan should be 
stored at room temperature, kept in a tightly closed container, and protected from light. 
7. Safety Reporting and Adverse Events 
All patients will have standard of care monthly clinic visits while on losartan.  Side 
effects and adverse events will be recorded by study coordinator at each clinic visit.  
Participants will have monthly complete metabolic profiles for monitoring of potassium, 
liver function tests.  Participants will be asked about symptoms of hypotension. 
Hyperkalemia: Participants will have potassium monitored monthly.  Potassium > 6 
mEq/L will be repeated and if abnormal, the dose of losartan will be decreased.  If 
participants are still >95th percentile blood pressure when hyperkalemia, a diuretic will 
be added as standard of care. 
Liver function tests: Participants baseline AST and ALT will be recorded and compared 
to monthly AST and ALT levels.  If AST/ALT is greater than three times the upper limit 
of normal, losartan will be stopped 
Symptomatic hypotension: Participants will be asked about symptoms of hypotension 
prior to enrollment and at each visit including feeling lightheaded or dizzy.  Participants 
will be asked to call the study PI to notify them of symptoms and take a blood pressure 
at home. 
Allergic reaction:  Participants will be asked to call the study PI if they develop swelling 
of the face, lips, throat, and/or tongue.  Participants will be asked to describe any new 
rashes. 
Musculoskeletal: Participants will be asked to describe any muscle pain, muscle 
tenderness, or dark urine. 


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Additional AEs will be documented based on participant interview and voluntary 
disclosure of additional toxicities.  AEs will be scored using the Common Toxicity 
Criteria for Adverse Events 4.0.   
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
Reporting of Events 
Serious safety events will be reported to the DSMB and IRB which will make 
recommendations to the study PI.  Unexpected SAE will be reported to the DSMB and 
IRB within 7 calendar days if fatal or life-threatening, and within 15 calendar days if not.  
All SAE will be provided to the DSMB quarterly.  All AE (serious and non-serious) will be 
reported to the DSMB every six months. 
Expected Adverse Events in Children with Sickle Cell Disease 
Acute chest syndrome 
Aplastic crisis 
Anemia 
Bacteremia 
Cholelithiasis, cholecystitis, biliary tract obstruction 
Dehydration 
Fever 
Gastroenteritis 
Headache 
Hematuria 
Hyposthenuira 
Hyperbilirubinemia 
Leukocytosis 
Nocturia 
Obstructive sleep apnea 
Osteomeylitis 
Otitis media 
Pain 
Pharyngitis 
Pneumonia 
Priapism 
Splenic sequestration 
Upper respiratory tract infections 
Urinary tract infections 
Tachycardia 


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Tachypnea 
Thrombocytosis 
 
Serious adverse event (SAE) 
Results in death 
Life-threatening (participant at risk of death at the time of the event) 
Requires or prolongs hospitalization (unless an expected event). 
Causes persistent or significant disability. 
Results in a congenital anomaly. 
Other medical events (in the opinion of the investigator) that may put the 
participant at risk or require intervention to prevent a serious AE. 
 
Potential Risks 
Losartan:  This medication is FDA approved to treat hypertension.  The FDA warnings include 
fetal toxicity (Pregnancy Category D) and Hypotension-Volume Depleted Patients.  Female 
participants will have monthly pregnancy tests performed and educated to stop Losartan 
immediately if pregnant.  Participants will be excluded if they are on a medication that leads to 
volume depletion (diuretics) and educated about volume depletion.  Precautions for losartan 
include 1)hypersensitivity (Angioedema)- participants will be educated on angioedema and 
immediately removed for life threatening events, 2) impaired hepatic function- participants will 
have monthly liver function tests, 3) impaired renal function in patients whose renal function 
depends on the renin-angiotensin-aldosterone system (i.e. CHF), 4) electrolyte imbalance- 
participants will have monthly electrolyte levels. 
Alternative treatments:  The alternative to participation in this trial is to have usual care, with an 
anti-hypertensive medication. 
Adequacy of protection against risks 
Phlebotomy:  Blood draws will be performed by trained personnel with expertise in pediatric 
phlebotomy and follow hospital standards for phlebotomy.  All blood obtained during this trial will 
be collected at the same time as standard of care labs to minimize extra risk of an additional 
blood draw.   
Urine samples:  Obtaining participant urine samples will follow hospital standards for urine 
collection and occur in a private setting 
History and physical exam:  Participants will undergo a monthly history and physical by an 
experienced sickle cell practitioner.    
Participant confidentiality:  To protect confidentiality, every participant will be assigned a study 
identification number that is unique.  The link between participant name and study ID will be 
kept on a locked, password protected computer that is separate from the locked, password 


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protected computer used to enter participant information.  All study forms will be entered using 
the study ID number.  Data will be retrieved using the study ID number.  
Data Safety and Monitoring Board 
We will identify investigators (at least 4 members to include a pediatric hypertension 
expert, sickle cell expert, patient representative, and biostatistician) to participate in an 
independent DSMB to monitor study safety and minimize research associated risk.  
Incidence of adverse events during the 6 month period will be analyzed during all 
mentoring meetings and independently by the DSMB.  The percentage and 95% 
confidence intervals for serious adverse events and adverse events will be recorded and 
sent to DSMB every 3 months.  The DSMB will evaluate excessive SAEs overall or in any 
one group and consider either: 1) reducing the dose of losartan or 2) closing the study 
and offering an alternative hypertensive medication.  Patients will be withdrawn from the 
trial if they experience angioedema, recurrent symptomatic hypotension despite dose 
reduction, hyperkalemia, or recurrent symptomatic hypoglycemia.   
 
8. ADHERENCE TO LOSARTAN 
8.1. Methods for Monitoring Adherence:  
Participants will complete a modified Morisky Scale of Adherence and ask open ended 
questions about adherence (qualitative measure of adherence).  Participants will be given 
a pill bottle of losartan dispensed by a study pharmacist with the number of dispensed 
pills recorded (1-5 extra pills dispensed each month) by the study monitor (quantitative 
measure of adherence).  Participants will return the pill bottles at each visit and the 
remaining pills will be counted to determine quantitative adherence to losartan. The study 
coordinator will place a reminder phone call to participants prior to their clinic 
appointment.   Adherence will be defined as taking at least 80% of losartan doses (23 
doses/4 weeks).  
8.2 Strategies to Promote Adherence:  
To evaluate the success of common strategies that promote adherence to losartan during 
the feasibility trial, all participants will be provided with a monthly study calendar that 
includes: dose/tablet number taken or missed dose, and side effects experienced that 
day.  Participants will be asked to complete and return the calendar.  Participants who do 
not return the calendar will be provided a stamped envelope to mail the calendar back to 
the study coordinator.  For patients that miss >20% doses (6 missed doses/4 wks), 
structured qualitative interviews will be conducted to identify individual barriers to 
adherence.   
8.3. Procedures for Missed appointments 
If a participant misses an appointment, the study team will immediately contact the participant 
using the most recently provided telephone number.  The study team will identify and record the 
cause for the missed appointment.  The study team will attempt to reschedule the appointment 


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as soon as possible.  All attempts to contact the participant and discussions with participant will 
be recorded in the patient record. 
9. SAMPLE SIZE AND STATISTICAL ANALYSIS 
9.1 Sample Size 
 An endpoint for this feasibility trial is to determine the effect size needed to 
appropriately power a definitive trial of losartan to correct nocturnal dipping, rather than 
efficacy of losartan.   Data will be collected to understand the acceptance rate, rate of 
recruitment, and the drop-out rate.  In preliminary fashion this feasibility trial will identify 
the difference in nocturnal BP improvement between the two treatment arms, and within 
group standard deviation of BP.  The feasibility trial will evaluate the change in nocturnal 
dipping % from baseline in all participants and among participants receiving two 
different dosing strategies (intensive losartan therapy  (BP <75th percentile) as 
compared to standard dosing (BP <95th percentile)).  Sample size analysis for repeated 
measures and adjustments to sample size to compensate for non-adherence will occur.  
The feasibility trial will enroll 40 participants with hypertension (clinic and ABPM).  It is 
expected that 30% of the 200 cohort participants will meet eligibility criteria.  Of these 60 
cohort participants, we expect that 40 participants will enroll in the feasibility trial.  We 
expect a dropout rate of <10% to ensure that the feasibility trial has > 30 participants, an 
accepted participant size for feasibility trials. 
9.2. 
Analysis: 
Objective 1: To demonstrate in a feasibility trial the optimal dose of losartan and effect 
size necessary to conduct a trial of losartan in participants with abnormal nocturnal 
dipping.   
Objective 2: Demonstrate the Acceptability of and Barriers to Enrollment into a 
Feasibility Trial of Losartan. 
Objective 3: Demonstrate and Promote Adherence to Study Medication during 
Feasibility Trial 
Objective 4: Demonstrate Adherence to Study Procedures and Retention in the Clinical 
Trial.   
Analysis for Objective 1: The feasibility trial will evaluate two dosing strategies of losartan.  
The DSMB will be instrumental in evaluating safety of losartan during the course of the 
trial.  At the end of the trial, the two dosing strategies for losartan will be directly compared 
using student’s t-test.  The effect size necessary to conduct a definitive trial will be 
obtained through identifying the acceptance rate (objective 2), adherence/dropout rate 
(objective 3 and 4).  The correction of abnormal nocturnal dipping will be evaluated using 


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continuous data.  To properly power a definitive trial, this feasibility trial will document the 
standard deviation/variability in BP among participants, the estimated difference in 
nocturnal blood pressure at baseline and exit.   
Analysis for Objective 2:  The acceptance rate will be defined by the percent of 
participants enrolled divided by the number of patients approached for enrollment.  The 
acceptability of the trial will be defined by evaluating barriers or facilitators to enrolling in 
this feasibility trial.  Dichotomous dependent variables will be created for participants that 
enroll or do not enroll in the study.  Independent variables will reflect (ordinal) responses 
provided during the survey. Bivariate relationships will be tested using chi-square or 
Fischer’s exact tests and/or logistic regression. The mentorship team will review the 
identified barriers and facilitators to enrollment and develop strategies to enhance 
enrollment in future BP trials.  For example, if mistrust is a barrier, a future strategy 
enrollment may include peer-delivered video testimonials. 
Analysis for Objective 3. Dr. Muntner will mentor Dr. Lebensburger in the analysis of 
medication adherence during a clinical trial.  Specifically, the adherence rates will be 
reviewed for each individual participant and for all participants over time to determine 
feasibility of losartan adherence over the six month trial.  In addition, the effect of 
adherence interventions (calendar, phone calls) on losartan will be reviewed as well as 
participant reasons stated for good/poor adherence.  The mentoring team will review 
adherence reports and work to develop an intervention plan for enhanced adherence 
during the planned definitive trial.   
Analysis for Objective 4: To effectively design a multicenter trial, it is vital to understand 
the rate and barriers to trial retention and feasibility of repeated ABPM prior to conducting 
a SCD hypertension trial.  The retention rate will be recorded and re-evaluated against 
the initial Likert surveys to identify variables that may suggest future drop-out.  The 
completion of ABPM at baseline, 3 months, and 6 months will be recorded, including days 
to return ABPM device.  Dr. Feig will mentor Dr. Lebensburger in analyzing the barriers 
in a hypertension trial.   
10. Consent/Assent Form 
  
The parent/legal guardian and participant will be given consent forms (and assent if participant 
is <14.0 yrs.) to read and sign prior to the participant’s entry into the screening and 
randomization phases, if eligible.  The consent and assent forms will be reviewed and approved 
by the IRB for content and general readability. The forms will provide participants and parents 
with an overview of the study objectives, a detailed description of all study 
procedures/evaluations, study medication side effects.  The forms will be given to participant, 
participant’s parent/legal guardian by an approved study team member.  The forms will be 
signed by the participant and parent/guardian as well as study team member and witness.  
11. Payment and Remuneration 
 
The participating families will receive $25 for each 24 ABPM performed 


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Costs 
The following will be paid for by the study: Shipping costs for ABPM and urine biomarker, ABPM 
analysis, urine biomarker analysis, and Losartan 
 
12. Inclusion of Women and Minorities 
The study should include a similar number of males and females, based on the sex of 
participants with HbSS and SB0 thalassemia seen at the Pediatric Hematology clinic.  We 
expect that most of our participants will be of African descent, given the ethnic distribution of 
SCD in the United States.  We will invite participants of other ethnic backgrounds to participate, 
if they meet the eligibility requirements for the study. 
13. Inclusion of Children 
We plan to enroll only children and adolescent patients with SCD ages ≥ 5 and < 23 years of 
age with hypertension.  
 
 
 
 
 
 


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CONSENT FORM 
 
TITLE OF RESEARCH: 
Chronobiology and Chronopharmacology to Prevent Sickle Cell 
Nephropathy 
 
IRB PROTOCOL NO.: 
IRB-141107009 
 
INVESTIGATOR: 
Jeffrey Lebensburger DO 
 
SPONSOR: 
National Institutes of Health (NIH) 
 
SUPPORT PROVIDED BY: 
American Society of Hematology (ASH) 
 
 
 
 
For Children (persons under 18 years of age) participating in this study, the term “You” 
addresses both the participant ("you") and the parent or legally authorized representative 
("your child"). 
 
Purpose of the Research 
We are asking you to take part in a research study. This research study will test how well a 
medicine to lower blood pressure helps young adults with sickle cell disease.  Losartan is a 
medication approved by the US Food and Drug Administration (FDA) to treat children and 
adults with high blood pressure.  If patients with high blood pressure are not treated, they may 
develop health problems including heart attacks, strokes, and kidney problems.  You are being 
asked to join this clinical trial since you have high blood pressure.  We could treat you with this 
same blood pressure medicine not on a clinical trial.  We would like you to participate in this 6 
month trial so we can learn how losartan may protect your kidneys.  We would also like to 
know the right dose of losartan for you.  Finally, we would like to learn more about how sickle 
cell disease may hurt your kidneys or cause high blood pressure.  After 6 months, we will 


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continue to treat your high blood pressure but will do so not on a trial. This study will enroll 60 
participants from UAB.  
 
Explanation of Procedures 
 
We will perform one more 24 hour blood pressure test to make sure you have high blood 
pressure.  High blood pressure means that your blood pressure is greater than 95 % of 
adolescents/young adults your age (95th percentile).  If you have high blood pressure, we will 
prescribe you an approved blood pressure medicine called Losartan.  The first dose will be 
administered in clinic to make sure no side effects occur.  The usual way to treat blood pressure 
is to get your blood pressure lower than the 95th percentile.  In other diseases, patients may do 
better if their blood pressure is not greater than than 75% of adolescents/young adults (75th 
percentile).   
 
If you enter the study, you will be randomly picked (like the flip of a coin) to receive either 
strategy (lower less than the 95th percentile or 75th percentile). The major goal of this study is to 
determine the safest and most effective way to treat high blood pressure in patients with sickle 
cell disease.   
 
When we start a blood pressure medication, we ask that you come to clinic every 4 weeks for 
the first 6 months to determine if the medicine is helping you or causing side effects.   At each 
visit you will be asked if you have had any bad reactions and how you are feeling on the 
medicine.  If your blood pressure during these clinic visits is in the normal blood pressure range, 
we will keep you on the same dose.  If your blood pressure is still too high, we will increase your 
dose.  We will also perform some blood and urine tests to make sure you are doing well on the 
medicine and how sickle cell may hurt your kidneys or cause high blood pressure.  Some of 
these tests will be done for research and others are normal tests while on a blood pressure 
medication.  For females, we must check if you are pregnant at each visit.    
 
The research tests on urine and blood will help us learn if the blood pressure medication is 
helping your kidneys.  The best way to study urine is to collect your urine overnight.  We will 
give you a urine container to collect your urine the night before three of your visits.  You will 
then bring your urine to clinic.  We may not be able to run these tests on the urine the day that 
you come to clinic so we will ask your permission to store your urine and blood in a research 
freezer.  We will only use your urine or blood to evaluate the role of high blood pressure in 
sickle cell disease.  Finally, we would like to learn about how your body handles sodium.  To do 
this test, we would ask you, on three different visits, to brush your cheek with a swab up to six 
times over 2 days. 
 
We would also like to learn how you feel about participating in a research study.  We would like 
to ask you to answer a few questions about what you like and don’t like about this trial.  If you 
enter this research study, we would also ask you questions each month about how often you 
take your medicine. 


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Version Date: 11/26/18 
 
After the 6 months, the study will be over.  We will continue to follow you and treat your blood 
pressure at regular visits.  
Standard Tests while on a blood pressure Medicine 
Test 
Entry 1 mo 2 mo 
3 mo 
4 mo 
5 mo 
6 mo 
Vital Signs, Hx and PE 
X 
X 
X 
X 
X 
X 
X 
CBC with diff 
X 
X 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
X 
X 
Ferritin 
X 
 
 
X 
 
 
X 
Cystatin C 
X 
 
 
X 
 
 
X 
Urine Microalbumin/Creatinine 
X 
 
 
X 
 
 
X 
Evaluate your  Adherence 
X 
X 
X 
X 
X 
X 
X 
Pregancy Test 
X 
X 
X 
X 
X 
X 
X 
 
Research Tests if you consent 
Test 
Entry 1 mo 
2 mo 
3 mo 
4 mo 
5 mo 
6 mo 
Uric Acid from collected blood 
X 
 
 
X 
 
 
X 
Urine and blood biomarkers 
X 
 
 
X 
 
 
X 
Overnight Urine Collection 
X 
 
 
X 
 
 
X 
24 hr Blood pressure  
X 
 
 
X 
 
 
X 
Buccal Cell Collection 
X 
 
 
X 
 
 
X 
Enrollment Survey 
X 
 
 
  
 
 
  
 
 
Risks and Discomforts 
 
This blood pressure medicine (Losartan) is FDA approved to treat high blood pressure in 
children.  You may have some side effects from taking this drug. The main side effect of 
Losartan is cough or a drop in blood pressure that you can feel.   
 
Losartan may alter potassium levels in the body.  We will check your potassium level monthly 
while on losartan.  If your potassium goes up, we can lower the dose or stop the medicine. 
Precautions for losartan include: allergic reactions (cough or swelling), muscle cramping, 
dizziness, abdominal or chest pain, nausea, headache, sore throat, diarrhea, poor sleep, sinus 
disorders.  There may also be risks that are unknown at this time. You will be given more 
information if other risks are found. 
 
You will be assigned to a treatment group by chance.  You will be either assigned to a group 
that lowers blood pressure to below the 95th percentile which may not be as effective in 
lowering blood pressure.  However, we have not proven that a higher dose of blood pressure 
medicine is better in sickle cell disease.  You may be assigned to the group that lowers blood 


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pressure to the 75th percentile.  This may require a higher dose of losartan.  This higher dose 
may cause you to have more side effects from the medicine. 
 
Information for Women of Childbearing Potential and/or Men Capable of Fathering a Child 
 
Losartan should not be taken if you are pregnant.  We will ask you not to become pregnant for 
the next 6 months.  We will check a pregnancy test at each visit.  If you are pregnant or become 
pregnant, there may be risks to the fetus.  This risk is highest during the 2nd or 3rd trimester.  
You must take a pregnancy test before the start of the study and at each visit to make sure you 
are not pregnant.  You must agree to an effective form of birth control when taking losartan. 
Effective birth control includes avoiding sexual activity that could cause you to become 
pregnant, birth control pills, patch, IUD, condom, sponge, or diaphragm with spermicide.  
 
Benefits 
 
You may not benefit directly from taking part in this study. However, this study may help us 
better understand how to treat high blood pressure in the future. 
 
Alternatives 
 
There are other drugs that are used to treat high blood pressure in children. The investigator or 
research staff will discuss these other drugs with you. 
 
Confidentiality 
 
Information obtained about you for this study will be kept confidential to the extent allowed by 
law. However, research information that identifies you may be shared with the UAB 
Institutional Review Board (IRB) and others who are responsible for ensuring compliance with 
laws and regulations related to research, including people on behalf of the NIH, ASH, and the 
Office for Human Research Protections (OHRP). The information from the research may be 
published for scientific purposes; however, your identity will not be given out.   
 
If any part of this study takes place at Children’s of Alabama, this consent document will be 
placed in your file at that facility. The document will become part of your medical record chart.    
Information relating to this study, including your name, medical record number, date of birth 
and social security number, may be shared with the billing offices of Children’s of Alabama and 
its billing agents so that the costs for clinical services can be appropriately paid for by either the 
study account or by the patient/patient’s insurance. Monitors, auditors, the Institutional 
Review Board for Human Use, and regulatory authorities will be granted direct access to your 
original medical records for verification of trial procedures and/or data without violating 
confidentiality. 


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 
Voluntary Participation and Withdrawal 
 
Whether or not you take part in this study is your choice. There will be no penalty if you decide 
not to be in the study. If you decide not to be in the study, you will not lose any benefits. You 
are free to withdraw from this study at any time. Your choice to leave the study will not affect 
your relationship with this institution. 
 
We may remove your from this study without your consent.  The study doctor may decide it is 
not in the best interest of your health.   
 
Cost of Participation 
 
There will be no additional cost to you for taking part in this study. Since you require a medicine 
for high blood pressure, the cost of coming to the clinic, having your blood pressure checked 
and labs checked will be billed to you and/or your insurance company in the usual manner.  We 
will pay for all of the research tests.  The medicine (Losartan) will be provided to you at no cost 
during the 6-month study period.  After the 6-month study period, the study will no longer pay 
for losartan.   
 
Payment for Participation in Research 
 
You will be paid $25 for each 24 hour ambulatory blood pressure performed.  You will have 
three of these tests performed during the study. If you complete the entire study, you will 
receive a total of $75 for blood pressure tests. 
 
You will be paid $25 for each overnight urine collection performed.  You will have three of these 
tests performed during the study.   If you complete the entire study, you will receive a total of 
$75 for urine tests. 
 
You will be paid $25 for each day you swab your cheeks.  You will have three of these tests 
performed during the study.   If you complete the entire study, you will receive a total of $75 
for cheek swabs. 
 
If you complete all of these tests, you will receive in total $225 
 
 


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Payment for Research-Related Injuries 
 
UAB, NIH and ASH have not provided for any payment if you are harmed as a result of taking 
part in this study. If such harm occurs, treatment will be provided. However, this treatment will 
not be provided free of charge. 
 
Significant New Findings 
You will be told by your doctor or the study staff if new information becomes available that 
might affect your choice to stay in the study. 
 
Questions 
 
If you have any questions, concerns, or complaints about the research or a research-related 
injury including available treatments, you may contact Dr. Jeffrey Lebensburger. He will be glad 
to answer any of your questions. Dr. Lebensburger’s number is 205-638-9285.  
 
If you have questions about your rights as a research participant, or concerns or complaints 
about the research, you may contact the UAB Office of the IRB (OIRB) at (205) 934-3789 or toll 
free at 1-855-860-3789. Regular hours for the OIRB are 8:00 a.m. to 5:00 p.m. CT, Monday 
through Friday. You may also call this number in the event the research staff cannot be reached 
or you wish to talk to someone else. 
 
Legal Rights 
 
You are not waiving any of your legal rights by signing this informed consent document. 
 
Storage of Specimens for Future Use 
 
In the future, we may have a better test to learn about the problems of high blood pressure in patients 
with sickle cell disease.  As part of this study, we would like to store some extra blood and urine for 
future research.  Dr. Lebensburger will decide if the blood or urine is used for a new test.  Dr. Jeffrey 
Lebensburger or by an IRB approved researcher may run the test. The urine and blood will be stored in a 
research freezer using a study ID.  Only Dr. Lebensburger will be able to identify you from this study ID. 
Results of future research may not be given to you. You do not have to agree to allow your blood and 
urine specimens to be stored in order to be part of this study. 
 
At any time, you can have your blood or urine removed from storage. Please contact Dr. Jeffrey 
Lebensburger at the University of Alabama at Birmingham at 205-638-9285. Once you contact Dr. 


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Version Date: 11/26/18 
Lebensburger, and if your samples have not already been used, they will be destroyed. If you do not 
make such a request, your specimens will be stored until used. 
 
Initial your choice below: 
 
___ I agree to allow my samples to be kept and used for future research high blood pressure and kidney 
disease in sickle cell. 
 
___ I do not agree to allow my samples to be kept and used for future research. 
 
 
 


Page 25 of 34 
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Signatures 
 
You are making a decision whether or not to have your child participate in this study. Your 
signature indicates that you have read (or been read) the information provided above and 
decided to allow your child to participate.  
 
You will receive a copy of this signed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant (14 years of age and older) 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Parent or Legally Authorized Representative (for participants less than 14)   Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent  
 
 
 
 
             Date 
 
 
 
 
Waiver of Assent 
 
The assent of ______________________________ (name of child/minor) was waived because 
of: 
Age _________ 
Maturity ________ 
 
Psychological state of the child ________ 
 
 


Page 26 of 34 
Version Date: 11/26/18 
University of Alabama at Birmingham 
AUTHORIZATION FOR USE/DISCLOSURE OF  
PROTECTED HEALTH INFORMATION (PHI) FOR RESEARCH 
 
Participant Name:   
 
 
 
UAB IRB Protocol Number:  IRB-141107009 
Research Protocol:  Chronobiology and 
Chronopharmacology to Prevent Sickle Cell Kidney 
Disease 
Principal Investigator:  Jeffrey D. Lebensburger, D.O. 
Sponsor:  The National Institutes of Health (NIH)/ 
American Society of Hematology (ASH) 
 
What is the purpose of this form?  You are being asked to sign this form so that UAB may use and release your 
protected health information for research.  Participation in research is voluntary.  If you choose to participate in the 
research, you must sign this form so that your protected health information may be used for the research. 
 
Why do the researchers want my protected health information?  The researchers want to use your protected health 
information as part of the research protocol listed above and as described to you in the informed consent. 
 
What protected health information do the researchers want to use?  All medical information, including but not 
limited to information and/or records of any diagnosis or treatment of disease or condition, which may include 
sexually transmitted diseases (e.g., HIV, etc.) or communicable diseases, drug/alcohol dependency, etc.; all personal 
identifiers, including but not limited to your name, social security number, medical record number, date of birth, 
dates of service, etc.; any past, present, and future history, examinations, laboratory results, imaging studies and 
reports and treatments of whatever kind, including but not limited to drug/alcohol treatment, 
psychiatric/psychological treatment; financial/billing information, including but not limited to copies of your medical 
bills,  and any other information related to or collected for use in the research protocol, regardless of whether the 
information was collected for research or non-research (e.g., treatment) purposes. 
 
Who will disclose, use and/or receive my protected health information?  All Individuals/entities listed in the 
informed consent documents, including but not limited to, the physicians, nurses and staff and others performing 
services related to the research (whether at UAB or elsewhere); other operating units of UAB, HSF, UAB Highlands, 
Children’s of Alabama, Eye Foundation Hospital, and the Jefferson County Department of Health, as necessary for 
their operations; the IRB and its staff; the sponsor of the research and its employees and agents, including any CRO; 
and any outside regulatory agencies, such as the Food and Drug Administration, providing oversight or performing 
other legal and/or regulatory functions for which access to participant information is required. 
 
How will my protected health information be protected once it is given to others?  Your protected health 
information that is given to the study sponsor will remain private to the extent possible, even though the study 
sponsor is not required to follow the federal privacy laws. However, once your information is given to other 


Page 27 of 34 
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organizations that are not required to follow federal privacy laws, we cannot assure that the information will remain 
protected. 
 
How long will this Authorization last?  Your authorization for the uses and disclosures described in this Authorization 
does not have an expiration date. 
 
Can I cancel this Authorization?  You may cancel this Authorization at any time by notifying the Principal Investigator, 
in writing, referencing the research protocol and IRB Protocol Number. If you cancel this Authorization, the study 
doctor and staff will not use any new health information for research. However, researchers may continue to use 
the protected health information that was provided before you cancelled your authorization. 
 
Can I see my protected health information?  You have a right to request to see your protected health information. 
However, to ensure the scientific integrity of the research, you will not be able to review the research information 
until after the research protocol has been completed. 
 
Signature of participant:   
 
 
 
 
 
 
 
Date:  
 
 
or participant's legally authorized representative:  
 
 
 
 
 
Date:  
 
 
Printed Name of participant’s representative:  
 
 
 
 
 
Relationship to the participant:  
 
 
 
 
 
 


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REFERENCES 
1. 
Gosmanova EO, Zaidi S, Wan JY, et al. Prevalence and progression of chronic kidney disease in 
adult patients with sickle cell disease. J Investig Med 2014:62(5):804-807. 
2. 
Hamideh D, Alvarez O. Sickle cell disease related mortality in the United States (1999-2009). 
Pediatr Blood Cancer 2013:60(9):1482-1486. 
3. 
Powars DR, Chan LS, Hiti A, et al. Outcome of sickle cell anemia: a 4-decade observational study 
of 1056 patients. Medicine (Baltimore) 2005:84(6):363-376. 
4. 
Abbott KC, Hypolite IO, Agodoa LY. Sickle cell nephropathy at end-stage renal disease in the 
United States: patient characteristics and survival. Clin Nephrol 2002:58(1):9-15. 
5. 
Warady BA, Sullivan EK. Renal transplantation in children with sickle cell disease: a report of the 
North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 
1998:2(2):130-133. 
6. 
McClellan AC, Luthi JC, Lynch JR, et al. High one year mortality in adults with sickle cell disease 
and end-stage renal disease. Br J Haematol 2012:159(3):360-367. 
7. 
Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: risk factors, 
clinical course, and mortality. Ann Intern Med 1991:115(8):614-620. 
8. 
Ojo AO, Govaerts TC, Schmouder RL, et al. Renal transplantation in end-stage sickle cell 
nephropathy. Transplantation 1999:67(2):291-295. 
9. 
Huang E, Parke C, Mehrnia A, et al. Improved survival among sickle cell kidney transplant 
recipients in the recent era. Nephrol Dial Transplant 2013:28(4):1039-1046. 
10. 
Marouf R, Mojiminiyi O, Abdella N, et al. Comparison of renal function markers in Kuwaiti 
patients with sickle cell disease. J Clin Pathol 2006:59(4):345-351. 
11. 
Haymann JP, Stankovic K, Levy P, et al. Glomerular hyperfiltration in adult sickle cell anemia: a 
frequent hemolysis associated feature. Clin J Am Soc Nephrol 2010:5(5):756-761. 
12. 
Aygun B, Mortier NA, Smeltzer MP, et al. Glomerular hyperfiltration and albuminuria in children 
with sickle cell anemia. Pediatr Nephrol 2011:26(8):1285-1290. 
13. 
McKie KT, Hanevold CD, Hernandez C, et al. Prevalence, prevention, and treatment of 
microalbuminuria and proteinuria in children with sickle cell disease. J Pediatr Hematol Oncol 
2007:29(3):140-144. 
14. 
McBurney PG, Hanevold CD, Hernandez CM, et al. Risk factors for microalbuminuria in children 
with sickle cell anemia. J Pediatr Hematol Oncol 2002:24(6):473-477. 
15. 
Gurkan S, Scarponi KJ, Hotchkiss H, et al. Lactate dehydrogenase as a predictor of kidney 
involvement in patients with sickle cell anemia. Pediatr Nephrol 2010:25(10):2123-2127. 
16. 
Becton LJ, Kalpatthi RV, Rackoff E, et al. Prevalence and clinical correlates of microalbuminuria in 
children with sickle cell disease. Pediatr Nephrol 2010:25(8):1505-1511. 
17. 
McPherson Yee M, Jabbar SF, Osunkwo I, et al. Chronic kidney disease and albuminuria in 
children with sickle cell disease. Clin J Am Soc Nephrol 2011:6(11):2628-2633. 
18. 
Imuetinyan BA, Okoeguale MI, Egberue GO. Microalbuminuria in children with sickle cell 
anemia. Saudi J Kidney Dis Transpl 2011:22(4):733-738. 
19. 
Alvarez O, Lopez-Mitnik G, Zilleruelo G. Short-term follow-up of patients with sickle cell disease 
and albuminuria. Pediatr Blood Cancer 2008:50(6):1236-1239. 
20. 
Dharnidharka VR, Dabbagh S, Atiyeh B, et al. Prevalence of microalbuminuria in children with 
sickle cell disease. Pediatr Nephrol 1998:12(6):475-478. 
21. 
Lebensburger J, Johnson SM, Askenazi DJ, et al. Protective role of hemoglobin and fetal 
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Mawanda M, Ssenkusu JM, Odiit A, et al. Micro-albuminuria in Ugandan children with sickle cell 
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in patients with sickle cell anemia. Pediatr Nephrol 2014. 
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Am J Hematol 2011:86(7):559-566. 
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Voskaridou E, Terpos E, Michail S, et al. Early markers of renal dysfunction in patients with sickle 
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Guasch A, Navarrete J, Nass K, et al. Glomerular involvement in adults with sickle cell 
hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc 
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27. 
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Dursun H, Bayazit AK, Cengiz N, et al. Ambulatory blood pressure monitoring and renal functions 
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Seeman T, Palyzova D, Dusek J, et al. Reduced nocturnal blood pressure dip and sustained 
nighttime hypertension are specific markers of secondary hypertension. J Pediatr 
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35. 
Dionne JM, Turik MM, Hurley RM. Blood pressure abnormalities in children with chronic kidney 
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Samuels J, Ng D, Flynn JT, et al. Ambulatory blood pressure patterns in children with chronic 
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37. 
Schmidt A, Gruber U, Bohmig G, et al. The effect of ACE inhibitor and angiotensin II receptor 
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38. 
Wurzner G, Gerster JC, Chiolero A, et al. Comparative effects of losartan and irbesartan on 
serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens 
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40. 
Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. 
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Okuguchi T, Osanai T, Fujiwara N, et al. Effect of losartan on nocturnal blood pressure in patients 
with stroke: comparison with angiotensin converting enzyme inhibitor. Am J Hypertens 
2002:15(11):998-1002. 
43. 
Yanagi M, Tamura K, Fujikawa T, et al. The angiotensin II type 1 receptor blocker olmesartan 
preferentially improves nocturnal hypertension and proteinuria in chronic kidney disease. 
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44. 
Smolensky MH, Hermida RC, Portaluppi F. Comparison of the efficacy of morning versus evening 
administration of olmesartan in uncomplicated essential hypertension. Chronobiol Int 
2007:24(1):171-181. 
45. 
Lv J, Ehteshami P, Sarnak MJ, et al. Effects of intensive blood pressure lowering on the 
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46. 
Group ET, Wuhl E, Trivelli A, et al. Strict blood-pressure control and progression of renal failure 
in children. N Engl J Med 2009:361(17):1639-1650. 
47. 
Balzano R, Lindblad YT, Vavilis G, et al. Use of annual ABPM, and repeated carotid scan and 
echocardiography to monitor cardiovascular health over nine yr in pediatric and young adult 
renal transplant recipients. Pediatr Transplant 2011:15(6):635-641. 
 
 
 


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ADHERENCE QUESTIONNAIRE 
 
 
1. Do you sometimes forget to take 
losartan? 
□Yes 
□No 
2. People sometimes miss taking 
their medication for reasons other 
than forgetting.  Thinking over the 
past two weeks, were there any days 
when you did not give your child 
his/her losartan? 
□Yes 
□No 
3. Have you ever cut back or stopped 
giving your losartan without telling 
your doctor because you felt worse 
□Yes 
□No 
4. When you travel or leave home, do 
you sometimes forget to bring along 
your losartan? 
□Yes 
□No 
5. Did you take your losartan 
yesterday? 
□Yes 
□No 
6. When you feel like your blood 
pressure is under control, do you 
sometimes stop taking losartan? 
□Yes 
□No 
7. Taking a medicine every day is a 
real inconvenience for some people.  
Do you ever feel hassled about 
sticking to your blood pressure 
treatment plan? 
□Yes 
□No 
8. How often do you have difficulty 
remembering to take all of your 
medicine? 
□Never/Rarely 
□Once in a while 
□Sometime 
□Usually 
□All the time 
9. How many doses have you missed 
since the last visit? 
 
 
________ 
 


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Version Date: 11/26/18 
ENROLLMENT SURVEY 
I/My child will enroll in 
this clinical trial 
□Yes 
□No 
You may have reasons to enroll or not enroll in this trial  
Please read the next 5 sentences and circle how much you agree with each 
reason 
I want to help doctors learn how to 
treat MY (my child’s) blood 
pressure 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I want to help doctors learn how to 
treat blood pressure for ALL 
children with sickle cell disease 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I want to make sure my (my child’s) 
blood pressure is closely monitored 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I want to make sure my (my child’s) 
blood pressure improves at night 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I want to prevent future problems 
with my (my child’s) kidneys 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
You may have reasons not enroll in this trial  
Please read the next 5 sentences and circle how much you agree with each 
reason 
I do not want (my child) to be in a 
clinical trial 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I do not want (my child) to take a 
blood pressure medicine 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I do not want (my child) to take this 
medicine (losartan) 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I do not have the time to come to 
clinic each month 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
I do not want (my child) to do the 
blood pressure cuff three more 
times 
Strongly Agree        Agree         
 
                Neutral     
 
 Disagree       Strongly Disagree 
 


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