Clinical trial NCT02225132
Conditions: Sickle Cell Disease
Keywords: Hydroxyurea Sickle Cell Disease Fetal Hemoglobin Induction
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2014-08-23; Completion date: 2018-05-24
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Sickle cell disease (SCD) is a blood disease. The drug hydroxyurea (HU) is approved to prevent pain crises in people with SCD. Researchers want to see how higher doses of HU affect the blood. This will help them learn about the right dosage of HU to give to people with SCD.

Objective:

\- To improve hydroxyurea dosing in people with SCD.

Eligibility:

\- People age 15 or older with homozygous SCD (HbSS).

Design:

* Participants will be screened with medical history, physical exam, medication review, and blood and urine tests.
* Participants will be in the study for about 15 months.
* First 3 months: monthly study visits with blood and urine tests.
* After 3 months: participants will take HU as a capsule by mouth. If you are already taking HU, your dose will be increased.
* Within a month of starting or increasing HU: participants will keep a daily pain diary for 2 weeks. They will have an echocardiogram (ultrasound) of the heart, a 6-minute walk test. They will complete a quality-of-life questionnaire.
* Participants will visit every month until they reach their highest tolerated dose of HU. They may need to come as often as every week sometimes to closely monitor their blood counts. Then they will alternate a phone call one month and a visit the next. At the visits, participants will bring their pill bottle, answer questions about side effects, and have blood tests.
* Every 2 months, participants will have a medical history, physical exam, and blood tests.
* Every 4 months, participants will have blood and urine tests. They will also complete another 2-week pain diary and quality-of-life questionnaire.
* About 12 months after starting or increasing HU, participants will have blood tests, an echocardiogram, and a 6-minute walk test.

Detailed description:
Sickle cell disease (SCD) is associated with significant morbidity and early mortality. Despite the discovery of the disease more than 100 years ago, only one drug, hydroxyurea (HU), has been FDA-approved. Hydroxyurea exerts its beneficial effects largely by inducing fetal hemoglobin (HbF) and thereby inhibiting red blood cell sickling. Hydroxyurea has been shown to decrease the frequency of acute complications such as painful crises and acute chest syndrome. However, previous studies are conflicting regarding whether HU improves survival; 2 long-term studies where HU was titrated to the maximum tolerated dose show that HU improves survival. However, multiple studies performed in the era post-FDA approval of HU show no change in median survival. We and others have found that patients with SCD who die prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our work also suggests that HU treatment per se is not sufficient to improve survival and decrease organ damage in patients with homozygous SCD (HbSS). Instead, patients treated with the highest HU doses and who had the highest HbF levels appeared more likely to survive and had less evidence of organ damage over time. Hydroxyurea management can be intimidating; therefore, many adults with HbSS are either not treated with HU or are treated with doses below that which are FDA-approved. A HU dosing algorithm may simplify dosing such that not only are more patients treated with HU, but more may be titrated to the maximal tolerated dose which may be necessary to prevent organ damage and prolong survival. Further, myelosuppression beyond what has traditionally been recommended may further maximize HbF response. This protocol is a prospective pilot study which follows a 2 month run-in period. Hydroxyurea dosing will be based on a written algorithm which will be derived manually, and by a computer program which was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic parameters will be monitored at baseline and after treatment to further study the effect of maximum HbF response on acute complications associated with HbSS and organ function.

Arms: arm 1: This is a one arm, open-label, non- randomized pilot study to evaluate the effect of algorithm- based HU dosing on the HbF response, the ability to titrate each patient to the MTD of HU, acute complications, and organ function in patients with HbSS.
Interventions: intervention 1: Hydroxyurea
Intervention descriptions: intervention 1: The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.

The mechanisms by which DROXIA produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

Protocol documents:
Prot_SAP_000.pdf: 
14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
1
CLINICAL RESEARCH PROJECT 
 
 
 
Protocol: 14-H-0172 
  
 
 
 
 
 
 
 
 
IND/IDE: Exempt 
 
NHLBI Protocol: Pilot Study to Assess Algorithm-Based Hydroxyurea Dosing in Subjects with Sickle 
Cell Disease 
  
Abbreviated Title: Algorithm Hydroxyurea Dosing 
 
Keywords: Hydroxyurea, dosing algorithm, fetal hemoglobin, sickle cell disease 
 
Principal Investigator and Accountable Investigator:   
Courtney D Fitzhugh MD, MCHB, NHLBI* (E) 
Molecular and Clinical Hematology Branch (MCHB)  
Building 10, Room 9N-112, NHLBI/NIH 
Bethesda, MD. 20892 
Phone:  (301) 402-6496 work 
Email:  fitzhughc@nhlbi.nih.gov 
 
 
 
 
  
Medically Responsible Investigator: 
John Tisdale, MD*  
 
 
301-402-6497 – 10/9N112 
 
NHLBI/MCHB (E) 
 
Associate Investigators: 
Hans Ackerman, MD, DPhil*            
  
NIAID/LMVR (E) 
Jordan Betz, PhD 
 
 
 
 
NHLBI/HB (V) 
Wynona Coles, RRT*  
 
 
 
NHLBI/MCHB (E) 
Anna Conrey, CRNP* 
 
 
 
NHLBI/CHB (E) 
Deepika Darbari, MD* 
 
 
 
NHLBI/HB (C) 
 
Cameron Fisher 
 
 
 
 
NHLBI/SCB (F) 
Matthew Hsieh, MD*  
 
 
 
NHLBI/MCHB (E) 
Mary Jackson, RN*  
 
 
 
NHLBI/DIR/OCD (E) 
Dachelle Johnson, PharmD 
 
 
 
CC/PHARM (E) 
Mihailo Kaplarevic, PhD 
 
 
 
NHLBI/DIR/OSD (E) 
Beth Link, RN*  
 
 
 
 
NHLBI/MCHB (E) 
Laurel Mendelsohn, BS 
 
 
 
HB, NHLBI (E) 
Josephine Mgaya 
 
 
 
 
HB, NHLBI (C) 
Jim Nichols, RN* 
 
 
 
 
NHLBI/HB (E) 
Constance Noguchi, PhD 
 
 
 
NIDDK/MMB (E) 
Purevdorj Olkhanud, MD, PhD 
  
NHLBI/SCB (E) 
Nermi Parrow, PhD  
 
 
 
NIDDK/DIR/DDB (F) 
Staci Martin Peron, PhD 
 
 
 
NCI/CCR/POB (E) 
Griffin Rodgers, MD  
 
 
 
NIDDK/OD (E) 
Katherine Roskom, RN, MSN* 
 
 
OCD, NHLBI (E) 
Alan Schechter, MD  
 
  
NIDDK/MMB (E) 
Tiffani Taylor  
 
 
 
 
NHLBI (E) 
Swee Lay Thein, MD, PhD, DSc 
 
 
NHLBI/HB (E) 
Kamille West, MD 
 
 
 
 
CC/ODDCC/TMD (E) 
Delon Wilson, MD 
 
 
 
 
NHLBI/SCB (F) 
*denotes who may obtain informed consent 


14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
2
 
NIH Research Coordinator:  
Mary Jackson, RN*  
 
 
 
NHLBI/DIR/OCD (E) 
 
 
Subjects of study: 
 
 
Number 
Sex 
 
 
Age range 
                                              
   
  24 
 
Male/Female 
 
>15 years              
 
 
 
Project involves ionizing radiation? 
 
 
No 
 
Off site project? 
 
 
 
 
No 
 
 
 
 
Multi-Institutional project? 
 
 
 
No 
 
 
DSMB involvement?  
 
 
 
No 
 
 
 
Tech Transfer: CRADA, MTA 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
3
Table of Contents 
1.0 
PRECIS ................................................................................................................................... 5 
2.0 
OBJECTIVES ......................................................................................................................... 5 
3.0 
BACKGROUND .................................................................................................................... 5 
3.1 
Pathophysiology .................................................................................................................. 5 
3.2 
Treatment Options ............................................................................................................... 6 
3.3 
Clinical and Scientific Justification..................................................................................... 7 
4.0 
STUDY DESIGN.................................................................................................................... 8 
5.0 
SUBJECT RECRUITMENT AND/ REGISTRATION ......................................................... 9 
5.1 
Recruitment efforts .............................................................................................................. 9 
6.0 
ELIGIBILITY ASSESSMENT .............................................................................................. 9 
6.1 
Inclusion Criteria ................................................................................................................. 9 
6.2 
Exclusion Criteria .............................................................................................................. 10 
7.0 
CLINICAL EVALUATION OF THE PATIENT ................................................................ 10 
7.1 
Pre-study evaluation will be performed under our screening protocol (08-H-0156) or our 
natural history study (04-H-0161) ............................................................................................... 10 
7.2 
On-study baseline evaluation and evaluation during the run-in period: ........................... 10 
7.3 
Evaluation prior to starting or increasing HU: .................................................................. 11 
7.4 
Outpatient monitoring ....................................................................................................... 11 
8.0 
TREATMENT PLAN ........................................................................................................... 11 
9.0 
RESEARCH STUDIES ........................................................................................................ 13 
9.1 
RBC deformability ............................................................................................................ 13 
9.2 
F-Cells and F-Reticulocytes .............................................................................................. 13 
9.3 
Cystatin C .......................................................................................................................... 13 
9.4 
Pain Diary .......................................................................................................................... 14 
9.5 
Quality of Life ................................................................................................................... 14 
10.0 SAMPLE COLLECTION, STORAGE AND TRACKING PLAN ..................................... 14 
10.1 
Sample storage ............................................................................................................... 14 
10.2 
Intended use ................................................................................................................... 14 
10.3 
Tracking ......................................................................................................................... 14 
10.4 
End of study procedures ................................................................................................ 14 
10.5 
Loss or destruction of samples ...................................................................................... 14 
10.6 
Publication Policy .......................................................................................................... 15 
11.0 DATA MANAGEMENT PLAN .......................................................................................... 15 
11.1 
Data collection ............................................................................................................... 15 
12.0 BIOSTATISTICAL CONSIDERATIONS ........................................................................... 15 
12.1 
Sample size .................................................................................................................... 15 
12.2 
Primary endpoint ........................................................................................................... 16 
12.3 
Secondary endpoints ...................................................................................................... 16 
12.4 
Study Analysis ............................................................................................................... 17 
12.5 
Stopping Rules ............................................................................................................... 18 
12.6 
Off study criteria ............................................................................................................ 18 
13.0 DATA AND SAFETY MONITORING PLAN ................................................................... 19 
13.1 
Data and Safety Monitoring .......................................................................................... 19 
14.0 HUMAN SUBJECT PROTECTION .................................................................................... 23 
14.1 
Rationale for Subject Selection ..................................................................................... 23 
14.2 
Participation of children ................................................................................................ 23 


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Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
4
14.3 
Rationale for the Exclusion of Pregnant Women .......................................................... 23 
14.4 
Participation of NIH Employees .................................................................................... 24 
14.5 
Risks and Discomforts ................................................................................................... 24 
14.5.1 Hydroxyurea .............................................................................................................. 24 
14.5.2 Phlebotomy and blood draws ..................................................................................... 25 
14.5.3 Quality of life questionnaire and pain diary .............................................................. 25 
14.5.4 Echocardiogram ......................................................................................................... 25 
14.6 
Risks in Relation to Benefits ......................................................................................... 26 
14.7 
Informed Consent Processes and Procedures ................................................................ 26 
14.8 
Conflict of Interest ......................................................................................................... 28 
15.0 PHARMACEUTICALS ....................................................................................................... 28 
15.1 
Hydroxyurea .................................................................................................................. 28 
16.0 
REFERENCES .............................................................................................................. 30 
APPENDIX A: NIH INFORMATION SHEET ON STAFF RESEARCH PARTICIPATION ..... 34 
 
 


14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
5
1.0 PRECIS 
Sickle cell disease (SCD) is associated with significant morbidity and early mortality.  Despite the 
discovery of the disease more than 100 years ago, only one drug, hydroxyurea (HU), has been 
FDA-approved.  Hydroxyurea exerts its beneficial effects largely by inducing fetal hemoglobin 
(HbF) and thereby inhibiting red blood cell sickling.  Hydroxyurea has been shown to decrease the 
frequency of acute complications such as painful crises and acute chest syndrome.  However, 
previous studies are conflicting regarding whether HU improves survival; 2 long-term studies 
where HU was titrated to the maximum tolerated dose show that HU improves survival.  However, 
multiple studies performed in the era post-FDA approval of HU show no change in median 
survival.  We and others have found that patients with SCD who die prematurely have more 
evidence of renal, hepatic, and cardiopulmonary damage.  Our work also suggests that HU 
treatment per se is not sufficient to improve survival and decrease organ damage in patients with 
homozygous SCD (HbSS).  Instead, patients treated with the highest HU doses and who had the 
highest HbF levels appeared more likely to survive and had less evidence of organ damage over 
time.  Hydroxyurea management can be intimidating; therefore, many adults with HbSS are either 
not treated with HU or are treated with doses below that which are FDA-approved.  A HU dosing 
algorithm may simplify dosing such that not only are more patients treated with HU, but more 
may be titrated to the maximal tolerated dose which may be necessary to prevent organ damage 
and prolong survival.  Further, myelosuppression beyond what has traditionally been 
recommended may further maximize HbF response.  This protocol is a prospective pilot study 
which follows a 2 month run-in period.  Hydroxyurea dosing will be based on a written algorithm 
which will be derived manually, and by a computer program which was developed at the NIH 
Clinical Center.  Clinical, laboratory, and echocardiographic parameters will be monitored at 
baseline and after treatment to further study the effect of maximum HbF response on acute 
complications associated with HbSS and organ function. 
 
2.0 OBJECTIVES 
 
2.1 Determine whether a hydroxyurea (HU) dosing algorithm leads to a statistically 
significant change in fetal hemoglobin (HbF) response as compared to baseline HbF in 
patients with homozygous sickle cell disease (HbSS).  The 95% confidence interval of 
the change will be calculated to see if the change is statistically significant. 
2.2 Determine whether maximum HbF response improves organ function in patients with 
HbSS.  
 
 
 
3.0 BACKGROUND 
 
3.1 
Pathophysiology  
 
Homozygous sickle cell disease was first described when sickled red blood cells (RBC) were 
found on a peripheral blood smear.1   Decades later, an abnormal hemoglobin was identified in 
patients with the disease.2  Sickle hemoglobin forms polymers upon deoxygenation3,4 and 
transforms RBC into rigid structures which occlude the microvasculature.  Vessel occlusion leads 
to acute complications such as recurrent painful crises and acute chest syndrome.  One study 
evaluated 232 patients with sickle cell disease (SCD) who completed a daily pain diary for up to 6 
months.5   While pain was reported in 54.5% of patient-days, only 3.5% of patient-days involved 
presentation to an emergency room, hospital, or clinic.  Therefore, patients frequently experience 


14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
6
pain at home without presenting for evaluation and treatment.  Patients may also experience 
chronic organ injury such as sickle nephropathy, sickle hepatopathy, and cardiopulmonary 
complications.  Further, organ damage has been associated with premature mortality in patients 
with HbSS.6-16  In a retrospective analysis involving our own cohort of patients with SCD with a 
mean follow-up of 3.6 years, deceased patients were more likely to have laboratory and 
echocardiographic evidence of organ injury at the time of enrollment and at most recent follow-up 
as compared to subjects remaining alive (Table 1).17  
 
Table 1: Multiple Logistic Regression Analysis of Variables Associated with Deceased Subjects 
Variablea 
Chi-Square Score 
P-value 
First Visit 
↑ Alkaline Phosphatase 
25.14 
<0.0001 
↑ Creatinine 
8.57 
0.02 
Last Visit 
↑ Direct Bilirubin 
11.43 
0.0007 
↓ Ejection Fraction 
4.16 
0.04 
↑ Tricuspid Regurgitant Velocity 
31.59 
<0.0001 
↑: Higher value is associated with deceased status.  ↓: Lower value is associated with deceased status. 
3.2 
 Treatment Options  
 
To date, HU is the only FDA-approved drug for the management of patients with HbSS.  The drug 
was approved based on the multi-center study of HU (MSH) where patients with HbSS were 
randomized to receive HU starting at a dose of 15 mg/kg/day and increased as tolerated to a 
maximum dose of 35 mg/kg/day or placebo.18  The trial was stopped early because patients who 
received HU had significantly decreased hospitalizations for pain crises and acute chest syndrome 
and had a decreased transfusion requirement.  Hydroxyurea was also found to significantly 
decrease the number of days that patients needed analgesic medications at home as compared to 
the placebo group.19   
 
HU largely exerts its effect by increasing HbF and inhibiting RBC sickling.20-23  Long-term HU 
studies further demonstrate improved survival.14,15  Conversely, studies from the post-HU 
approval era found that patients continue to die by the fifth decade of life.9,12,13,16,24  Further, health 
database studies have shown no significant change in mortality rates between the years before and 
after HU approval.16,25  However, HU dosing was not considered by these studies, and only 7-37% 
of patients were prescribed HU at the time of death.9,12,13,24  When we retrospectively queried data 
regarding patients with SCD screened at the NIH, we found that HU dosing was independently 
associated with prolonged survival (p=0.006).26,27   
 
Lastly, our recent retrospective analysis suggests that patients with the highest HbF response were 
more likely to survive and also had less evidence of organ damage over time.  The mean HbF seen 
throughout the period of follow-up in the highest HbF quartile group was 26 as compared to 1.5% 
in the lowest HbF quartile group, and the median HU doses were 24.1 versus 4.8 mg/kg/day, 
respectively26,27.  Patients in the highest HbF quartile group had less evidence of renal, hepatic, 
and cardiopulmonary dysfunction at enrollment and most recent follow-up as compared to the 
lowest HbF quartile group (Table 2).  


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Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
7
 
Table 2: Comparison of Organ Function Parameters in Patients with HbSS Based on HbF Quartile 
 
First Visit 
Last Visit 
Variable 
Low 
HbF 
High 
HbF 
P-value 
Low 
HbF 
High 
HbF 
P-value 
Ejection Fraction (%) 
56.2 
59.9 
0.004 
57.5 
60.2 
0.04 
Alanine Aminotransferase 
(U/L) 
34.6 
25.7 
0.01 
38.9 
28.5 
0.03 
Aspartate Aminotransferase 
(U/L) 
52.0 
41.4 
0.04 
54.7 
33.7 
<0.0001 
Creatinine 
1.7 
0.7 
0.002 
2.0 
0.9 
0.004 
 
 
A study performed in infants with HbSS which employed a fixed dose of HU at 20 mg/kg/day did 
not meet the primary endpoints of preventing organ damage.28  However, a small case series 
reported splenic regeneration in patients with HbSS when HbF increased to 30%.  These results 
were supported by two larger pediatric studies where patients were treated with maximally 
tolerated doses of hydroxyurea,29,30 one confirming that HbF 25% was more likely to be associated 
with some splenic uptake as compared to HbF 14%.30  It is possible that HbF approaching 30% 
may be crucial to prevent organ injury caused by sickled RBC-induced vascular damage.8,31,32  
However, improvement in secondary markers of splenic function seen in the infant study28 
suggests that even modest increases in HbF can be beneficial. 
 
Multiple studies have evaluated medication adherence in patients who take HU.  The MSH study 
evaluated adherence by counting capsules that were left in bottles, percentage of clinic visits that 
were kept, serum HU levels, and percentage of patients who reached toxic myelosuppression.33  
Adherence was defined as administering at least 80% of capsules and keeping at least 80% of 
clinic visit appointments.  They found that patients with HbF levels in the highest quartiles had 
medication adherence rates ranging from 81-83%.  Conversely, adherence rates were 56 to 71% in 
patients in the lowest HbF quartiles.  Other studies have reported adherence rates ranging from 35-
58% in 2 studies34,35 to 75-88.9% in 3 studies.36-38  As expected, adherence rates were higher in the 
last 3 studies since patients were followed prospectively as compared to the previous 2 studies 
which were retrospective analyses. 
 
3.3 
Clinical and Scientific Justification 
 
The most common indications for HU initiation in patients with HbSS are recurrent pain crises 
and acute chest syndrome.  Hydroxyurea has also been used in patients with severe anemia since it 
significantly improves hemoglobin levels.  The most frequent adverse effect associated with HU is 
myelosuppression.  The MSH study permitted HU titration as long as the following parameters 
were not met: absolute neutrophil count (ANC) less than 2,000/uL and an absolute reticulocyte 
count (ARC) and platelet count less than 80,000/uL or a dose of 35 mg/kg/day.18  These 


14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
8
parameters now define what is considered the maximum tolerated dose (MTD) in standard clinical 
practice.  Only 65% of patients with HbSS screened at the NIH Clinical Center were treated with 
HU despite the vast majority meeting disease criteria severe enough to warrant initiating HU.  
Because we are a referral center and most patients are managed by their outside hematologist, we 
have not been able to control what percentage of patients who are followed at outside institutions 
start HU.  However, as ANC ranged from 5,600 to 4,900/uL, ARC ranged from 267,000 to 
222,800/uL, and platelet count ranged from 399,700 to 353,100/uL between patients who had ever 
administered HU at the time of enrollment and at most recent follow-up, respectively, MTD was 
not reached in our cohort.  Further, the median HU dose in all patients with HbSS was only 19.4 
mg/kg/day.   In the MSH study, only 33% of patients in the HU group were administering HU at 
MTD or had received a higher dose that was later decreased within 6 months of initiating HU.18  
By the end of the study, 51% of the patients were on a MTD or close to maximal dose.   
 
Since the definition of MTD based on blood counts was arbitrary, it may be necessary to tolerate 
lower blood counts in order to maximize HbF induction.  In the most recent years, we at the NIH 
have been tolerating an ANC as low as 1,500/uL when titrating HU dosages in patients with 
HbSS.  The goal has been to start HU at 15 mg/kg/day and increase the dose by 5 mg/kg every 2 
months until MTD is reached.  However, due to the complexity involved in their care, often the 
focus has not been to push the HU to MTD.  Ideally, a dosing algorithm would make the HU dose 
titration process easier, more effective, and less intimidating for primary providers who frequently 
manage adult patients with HbSS.  Further, a computer program which is able to calculate a HU 
dose based on patients’ blood counts and the timing of most recent HU dose titration would 
improve the percentage of patients whose HU is increased to MTD.  Proof of principle is 
evidenced by multiple computer-based warfarin dosing studies which increased confidence 
regarding warfarin dosing for doctors and nurses, decreased the number of venipunctures, and 
either produced dosing results that were equal to or superior to manual dosing 
recommendations.39-41   
 
As described above, HU has been shown to decrease acute complications associated with SCD.  
Further, HU, particularly when pushed to MTD and thereby maximizing HbF response, may 
improve survival and prevent organ damage.  While HU commonly leads to myelosuppression, 
other serious side effects are rare.  There has been no evidence that HU increases the risk of 
secondary malignancies above that in the general population of patients with HbSS.42  Therefore, 
treatment of all adult patients with HbSS, and not just those with recurrent acute complications, is 
justified.  
 
4.0 STUDY DESIGN 
 
This is a one arm, open-label, non-randomized pilot study to evaluate the effect of algorithm-based 
HU dosing on the HbF response, the ability to titrate each patient to the MTD of HU, acute 
complications, and organ function in patients with HbSS. The primary outcome will be the change 
of HbF level from baseline with algorithm-based HU dosing.  The detailed definitions about 
primary endpoints and secondary endpoints are given in Section 12.0. 
 
The study will follow a 2 month run-in period during which time 3 visits will occur (first visit and 
then another visit 1 and 2 months later).  During the run-in period, patients will remain off of HU 


14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
9
or continue their current dose of HU, and baseline data will be gathered.  Patients will then be 
treated with HU for 1 year according to a dosing algorithm.   
 
The IT and computational support is provided by the NHLBI DIR Scientific Information Office, 
and Information Technology and Applications Center. The program features a Php/HTML built 
front-end and a MySQL database in the background.   Hydroxyurea doses will be derived 
manually according to the written algorithm and also be determined by the computer program.   
 
A licensed independent practitioner (LIP) or pharmacist will review laboratory data for all patients 
on this protocol.   
 
Samples will be collected to monitor HbF, red blood cells with HbF (F-cells), and reticulocytes 
with HbF (F-reticulocytes).  Frequency of hospitalizations and transfusion requirements will be 
monitored as well as pain scales and quality of life.  Further, as we found that patients with renal, 
hepatic, and cardiopulmonary dysfunction were more likely to die prematurely and there was also 
evidence that HU may prevent or reverse damage involving those organs, renal, hepatic, and 
cardiopulmonary function will be monitored closely.  To assess kidney function, urine albumin 
and protein, urine osmolality, serum creatinine, glomerular filtration rate (GFR), and cystatin C 
will be monitored.  Regarding the liver, alkaline phosphatase, direct bilirubin, transaminases, and 
gamma-glutamyl transpeptidase (GGT) will be followed.  To evaluate cardiopulmonary function, 
ejection fraction, tricuspid regurgitant velocity (TRV), pro-brain natriuretic peptide (BNP), 6 
minute walk distance, and oxygenation with ambulation will be followed.   
                 
5.0 SUBJECT RECRUITMENT AND/ REGISTRATION 
 
5.1 
Recruitment efforts 
 
The study will be listed on the clinicaltrials.gov, Clinical Center research studies, and the National 
Heart, Lung and Blood Institute patient recruitment websites.  We will also ask local providers 
who follow patients with HbSS such as Howard University Hospital and Children’s National 
Medical Center to refer patients.  Further, local patients who are followed on our National History 
Study and our Screening Study will be asked to participate in this study.  If at least 6 patients are 
not enrolled every 6 months, a recruitment plan will be developed by the Clinical Center Office of 
Patient Recruitment.  
 
6.0 
ELIGIBILITY ASSESSMENT 
  
6.1 
Inclusion Criteria 
 
6.1.1 Age > 15 years 
6.1.2 Homozygous sickle cell disease (HbSS) 
6.1.3 Patients with recent transfusion must have HbA <15% prior to enrollment 
6.1.4 ANC >2,000/uL, platelets >150,000/uL, Hb >5.4g/dL, and ARC >100,000/uL 
(unless the Hb is >8g/dL) at baseline 
6.1.5 Patients on angiotensin-converting enzyme inhibitors and angiotensin receptor 
blockers should be on a stable dose for 2 weeks prior to initiating or adjusting HU 
 


14-H-0172 
Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
10
6.2 
Exclusion Criteria 
 
6.2.1 Pregnant or lactating women or patients planning to get pregnant during the study 
period 
6.2.2 Patients unwilling to use two forms of contraception throughout the period of HU 
administration 
6.2.3 Patients receiving chronic transfusion therapy 
6.2.4 Patients receiving a HU dose of >20 mg/kg/day 
6.2.5 Patients with history of allergy or intolerance to HU judged by the investigator to 
be prohibitive against restarting HU 
6.2.6 Patients with end stage renal disease defined as GFR <10mL/min/1.73m2 
6.2.7 Patients being treated with antiretroviral agents (such as didanosine and stavudine) 
because of a higher risk for potentially fatal pancreatitis, hepatic failure, hepatitis, 
and severe peripheral neuropathy when co-administered with hydroxyurea. 
6.2.8 Participation on any other chronic investigative treatment studies  
6.2.9 Unable to understand the investigational nature of the study or give informed 
consent 
 
7.0 
CLINICAL EVALUATION OF THE PATIENT 
 
7.1 
Pre-study evaluation will be performed under our screening protocol (08-H-0156) or 
our natural history study (04-H-0161) 
7.1.1 History and physical examination 
7.1.2 CBC with differential, ARC 
7.1.3 Hemoglobin electrophoresis 
7.1.4 Acute care panel, hepatic panel 
7.1.5 HIV antibody 
7.1.6 Urine or serum pregnancy test in women of childbearing potential 
7.1.7 Eligible patients will sign informed consent 
 
7.2 
On-study baseline evaluation and evaluation during the run-in period:  
The following studies will be repeated every month +/- 7 days for a total of 2 months: 
7.2.1 CBC with differential, ARC 
7.2.2 Hemoglobin electrophoresis, F-cells, F-reticulocytes 
7.2.3 Acute care panel, hepatic panel, GGT, BNP, cystatin C, lactate dehydrogenase 
(LDH), Erythropoietin (EPO) 
7.2.4 GFR: The following equation will be used to calculate GFR (Chronic Kidney 
Disease Epidemiology Collaboration, CKD-EPI)43-45 
 
GFR (mL/min/1.73 m2) = 141 x min(Scr/k, 1)α x max(Scr/k, 1)-1.209 x 0.993Age x 
1.018 (if female) x 1.159 (if African-American) where Scr is serum creatinine, k is 
0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min 
indicates the minimum of Scr/k or 1, and max indicates the maximum of Scr/k or 1.  
 
7.2.5 Urine protein/creatinine ratio, urine albumin/creatinine ratio, urine osmolality 
 


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7.3 
Evaluation prior to starting or increasing HU:  
The following studies will be performed within one month +/- 7 days of starting or increasing HU 
unless otherwise indicated: 
7.3.1 A pain diary which surveys pain intensity on a 0-10 scale and medications required 
will be completed at home daily for a 2 week period  
7.3.2 Transthoracic echocardiogram  
7.3.3 6-minute walk 
7.3.4 PROMIS quality of life questionnaire (see Section 9.6) 
7.3.5 The concentration of HbF within F-cells 
7.3.6 RBC Deformability 
7.3.7 Urine or serum pregnancy test will be performed in women of childbearing 
potential within 48 hours of ordering the first dose of HU in patients not already 
taking HU 
7.4 
Outpatient monitoring 
7.4.1 Patients will have CBC with differential and ARC drawn 2 weeks +/- 7 days after 
every HU dose adjustment 
7.4.2 Patients will be seen once monthly +/- 7 days before MTD is reached to check pill 
count, to continue to encourage compliance, and to evaluate for adverse effects 
7.4.3 CBC with differential, hemoglobin electrophoresis, ARC, acute care panel, and 
hepatic panel will be checked once monthly +/- 7 days until patients reach MTD 
7.4.4 History and physical will be performed every 2 months +/- 7 days 
7.4.5 CBC with differential, hemoglobin electrophoresis, ARC, acute care panel, and 
hepatic panel will be checked every 2 months +/- 7 days after patients reach MTD 
7.4.6 After reaching MTD, patients will be called every month that they are not seen in 
clinic to encourage compliance with HU administration 
7.4.7 F-cells, F-reticulocytes, the concentration of HbF within F-cells, RBC 
Deformability, GGT, BNP, LDH, EPO, cystatin C, GFR, urine protein/creatinine 
ratio, urine albumin/creatinine ratio, and urine osmolality will be checked every 4 
months +/- 7 days 
7.4.8 Urine or serum pregnancy test will be checked in women of childbearing potential 
every 4 months +/- 7 days 
7.4.9 A pain diary will be completed at home daily for a 2 week period every 4 months 
+/- 7 days 
7.4.10 PROMIS quality of life questionnaire will be performed every 4 months +/- 7 days 
(see Section 9.6) 
7.4.11 Transthoracic echocardiogram will be performed at 12 +/- 1 month 
7.4.12 6-minute walk will be performed at 12 +/- 1 month 
8.0 TREATMENT PLAN 
 
The dosing algorithm is as follows: 
 
1) Starting dose:  Normal renal function- 15 mg/kg/day (rounded to the nearest 200, 300, or 500 
mg capsule), given in a single daily dose.  Abnormal renal function (10 to 60 mL/min/1.73m2) 
7.5 mg/kg/day46 (rounded to the nearest 200, 300, or 500 mg capsule). 
 


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12
2) Patients already receiving/taking HU will initially stay on their current dose unless the dose is 
less than the starting dose above. 
 
3) If tolerated for at least 8 weeks without toxicity, increase HU dose by 5 mg/kg/d in patients 
with normal renal function and 2.5 mg/kg/d in patients with abnormal renal function and 
monitor as above (up to a maximum of 35 mg/kg/day).  The weight of the patient at the time of 
the HU adjustment will be used to calculate the next dose. 
 
4) Check complete blood count (CBC), differential, and absolute reticulocyte count (ARC) two 
weeks after every dose adjustment. 
a) Stop HU if any of the following are detected on CBC: 
i) ANC <1,500/uL 
ii) Platelets <80,000/uL 
iii) Hb <5.4 g/dL 
iv) ARC <80,000/uL only if Hb < 8 g/dL 
b) If HU is held, recheck CBC and ARC within 1-2 weeks.  If counts are above toxicity 
parameters, restart at the same dose. 
c) If the blood counts are still abnormal after 1-2 weeks, recheck again in 1-2 weeks.  If 
counts are above toxicity parameters, restart at the same dose. 
d) If toxicity recurs or persists, stop as above, and later resume therapy with a dose reduced 
by 2.5 mg/kg/day. 
 
5) Blood counts will be repeated 4-5 weeks after every dose adjustment. 
a) The same holding parameters will then be followed as described above. 
 
6) If we are unable to complete evaluations listed above as scheduled due to subject experiencing 
a complication such as vaso-occlusive crisis, then the evaluations will be done at the subject’s 
next study visit.  
 
7) Subjects will be provided with a reserve supply, with a maximum of 7 doses of HU at each 
visit to ensure that they will not run out of study drug in between study visits.  If they have not 
used the reserve supply provided from the previous visit, then no additional reserve supply will 
be provided.   
 
8) If total Hb increases to >12 g/dL, patients are at risk for hyperviscosity.  Therefore, serum 
ferritin will be checked and one unit of blood can be phlebotomized up to every 14 days to 
keep hemoglobin <12 g/dL.  If hemoglobin remains above 12 g/dL after 2 phlebotomy 
attempts, HU dose will be decreased by 2.5 mg/kg/d. 
 
9) If a patient experiences intolerable (defined as grade 2 or higher) gastrointestinal toxicity 
(vomiting and/or diarrhea) that is not helped by anti-emetics, the prescribed daily dose will be 
divided and administered twice daily.  If the patient continues to have grade 2 or higher 
gastrointestinal toxicity after the dose is divided, then the hydroxyurea dose will be decreased 
by 2.5 mg/kg/d. 
 
10) Patients must be at least 70% compliant during the 8 week period in order for the HU dose to 
be increased. 


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August 23, 2016 (Amendment O)  
13
11) Toxicity is defined as significant myelosuppression as defined in section 8.0, #4a or total Hb 
that remains >12 g/dL despite 2 phlebotomy attempts as stated in section 8.0, #6. 
 
12) MTD is defined as 2.5 mg/kg/d lower than the dose that reaches toxicity after 2 different 
attempts OR 2.5 mg/kg/d lower than the dose that takes more than 2 weeks to recover counts 
OR 2.5 mg/kg/d lower than the dose that causes grade 2 or higher gastrointestinal toxicity 
despite splitting the dose OR a dose of 35 mg/kg/d. 
 
13) The results of pregnancy tests will be reviewed by either the LIP, research nurse, or 
pharmacist. The study drug will be ordered prior to obtaining the test results, but will not be 
dispensed until the results are reviewed. 
 
14) Hydroxyurea may be held or the dose may be split into two equal doses for adverse events at 
the discretion of the PI, until the AE sufficiently resolves. The PI will consider the nature of 
the adverse event and the likely relation to drug therapy to make a determination of whether to 
restart at the same dose level or reduce the dose, or recommend discontinuation of HU and 
removal from the protocol. 
 
Patients will be followed at the NIH for 1 year after HU initiation or dose increase.  If a subject 
develops an acute vaso-occlusive crisis requiring hospitalization during that time, they will be 
encouraged to return to the NIH Clinical Center for admission, where they will receive standard of 
care.  After patients complete the one year period of the study drug, they may be enrolled on to a 
different protocol if available or HU management will be transitioned to their primary 
hematologist. 
 
9.0 RESEARCH STUDIES 
 
9.1 
RBC deformability 
Decreased deformability is a characteristic of erythrocytes from patients with SCD.  
Ektacytometry allows for the determination of red cell shape in response to defined shear stresses. 
Methods have recently been reported that correlate deformability characteristics and number of 
irreversibly sickled cells or percentage of HbS47.  The deformability and aggregation 
characteristics of red blood cells will be monitored at baseline and every 4 months +/- 7 days by 
ektacytometry.  Data will be analyzed in terms of both absolute deformability and deformability as 
a function of hemoglobin composition. 
 
9.2 
F-Cells and F-Reticulocytes 
The percentage of red blood cells and reticulocytes that contain HbF will be monitored at baseline 
and every 4 months +/- 7 days.  We will also assess the percentage of HbF within F-Cells since the 
F-Cells with the highest percentage of HbF are more likely to inhibit sickle hemoglobin 
polymerization.47 
 
9.3 
Cystatin C 
Cystatin C is a ubiquitous protein that is freely filtered at the glomerulus and not reabsorbed.  
After filtration, it is catabolized and is not detected in the urine.  Serum cystatin C-based GFR may 
be a more accurate measurement for GFR as compared to creatinine-based GFR in patients with 
SCD.48  Cystatin C will be measured at baseline and every 4 months +/- 1 week. 


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Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
14
9.4 
Pain Diary 
A pain diary will be administered which will evaluate a pain intensity score from 0-10 and pain 
medications required.  These measurements will be collected daily over a 2 week period.19   A 
comprehensive pain score will be calculated by adding these pain scores over each two week time 
period.  Pain diaries will be administered at baseline and every 4 months +/- 1 week. 
 
9.5 
Quality of Life 
PROMIS quality of life questionnaire will be administered at baseline and every 4 months +/- 1 
week.  The specific forms that will be used are the Pain Interference - Short Form 8a, Fatigue- 
Short Form 8a, Ability to Participate in Social Roles and Activities- Short Form 8a, and Physical 
Function- Short Form 8b.  Each of the PROMIS short forms will be administered in paper and 
pencil format, and each takes less than five minutes to complete.  Each of the PROMIS short 
forms has items on a 5-point Likert scale.  The total raw score is derived from summing the 
individual item responses, and raw scores are converted to standardized t-scores, with a mean of 
50 and standard deviation of 10. 
 
10.0 
SAMPLE COLLECTION, STORAGE AND TRACKING PLAN 
 
10.1 
Sample storage 
Research samples will have patient identifiers and be stored in the secure laboratory of the principal 
investigator or Core Lab. The PI will be responsible for overseeing entry of data into an in-house password 
protected electronic system.  Research samples will be stored using BSI in accordance with NHLBI 
DIR Biospecimen policy. 
 
Data gathered via the computer program will be stored in a MySQL database.  Access to the computer 
program is password protected through the standard NIH portal.   
10.2 
Intended use 
During the course of participating on this study, blood and data will be collected for correlative 
laboratory research studies.  Specimens collected strictly for research purposes will not be read by 
a pathologist.   
 
10.3 
Tracking 
Samples will be ordered and tracked through CRIS Research Screens.  Should a CRIS screen not 
be available, the NIH form 2803-1 will be completed and will accompany the specimen and be 
filed in the medical record.   
 
10.4 
End of study procedures 
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. 
 
10.5 
Loss or destruction of samples 
Should we become aware that a major breech in our plan for tracking and storage of samples has 
occurred, the IRB will be notified. 
 


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15
10.6 
Publication Policy  
Given the research mandate of the NIH, patient data including the results of testing and responses 
to treatment will be entered into an NIH-authorized and controlled research database. Any future 
research use will occur only after appropriate human subject protection and institutional approval 
such as prospective NIH IRB review and approval or an exemption from the NIH Office of 
Human Subjects Research (OHSR).  Data will not be sent outside the NIH without IRB 
notification and an executed MTA or CTA. 
 
11.0 
DATA MANAGEMENT PLAN 
 
11.1 
Data collection 
The PI will be responsible for overseeing entry of these data into an in-house password protected 
electronic system and ensuring data accuracy, consistency, and timeliness. The principal 
investigator and associate investigators, research nurses and/or a contracted data manager will 
assist with the data management efforts.  
 
All human subjects personally identifiable information (PII) as defined in accordance to the Health 
Insurance Portability and Accountability, eligibility and consent verification will be recorded.  
Primary data obtained during the conduct of the protocol will be kept in secure network drives or 
in approved alternative sites that comply with NIH security standards.  Primary and final analyzed 
data will have identifiers so that research data can be attributed to an individual human subject 
participant, (e.g., study-specific identifying number [SSPIN]) or other unique code, or minimum 
PII required for subject identification.  PII will not be contained within the computer program; 
instead, study identifiers will be used to keep track of HU dosing information, weight, blood 
counts, and kidney function.  
 
12.0 
BIOSTATISTICAL CONSIDERATIONS  
 
12.1 
Sample size 
The sample size is estimated based on comparison of the HbF change from baseline to year 1 with 
no change.  Based on data from our previous studies, the mean absolute change in HbF (measured 
in percentage) at months 8, 10, and 12 from baseline is about 11% with a standard deviation of 
change of about 10% for patients with standard HU dosing.  With the assumption of HbF change 
for this study being of a similar magnitude and using a paired t-test, a sample of 9 will be needed 
for this single arm study to achieve 83% power at a significance level of 0.05 on testing the null 
hypothesis that there is no significant difference between the baseline and year 1 HbF after the 
algorithm-based dosing.  The sample size calculation was performed in SAS 9.3, using the power 
procedure. 
 
We assume that up to 30% of patients will be noncompliant (defined as missing >20% of pills 
within one month on at least 2 occasions).  Further, because red blood cell transfusion may 
suppress HbF, frequent transfusions may interfere with HU response.  Based on our current cohort 
of 71 patients that we follow consistently, up to 20% of patients receive more than 2 transfusions 
per year.  Therefore, we assume that up to 20% of patients will receive more than 2 transfusions 
per year.  So the total dropout rate is expected to be up to 60%. To account for this, a sample size 
of 24 patients would be needed.  Those patients who receive more than 2 transfusions per year or 
who are noncompliant as described above will be discontinued from the protocol. 


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Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
16
Parameters to be followed: 
a. HbF, F-cells, F-reticulocytes 
b. ANC, Hb, MCV, platelet count, ARC 
c. Cr, AST, ALT, total bilirubin, direct bilirubin, GGT, LDH, EPO 
d. GFR, cystatin C 
e. Urine osmolality, urine protein/creatinine ratio, urine albumin/creatinine ratio 
f. Ejection fraction, TRV, BNP 
g. 6 minute walk distance, oxygen saturation at baseline and after walking for 6 minutes 
h. Frequency of analgesics used at home and comprehensive pain score 
i. Quality of life 
j. Frequency of hospitalization for pain crises and acute chest syndrome 
k. Transfusion requirement 
l. Medication compliance, frequency of medication refills, and compliance with clinic visits 
m. RBC deformability 
 
12.2 
Primary endpoint 
The difference between the mean HbF calculated at baseline (from the 3 values obtained during 
the run-in period (at the first visit and then again 1 and 2 months later)) as compared to the mean 
HbF calculated from 3 values obtained at months 8, 10, and 12. 
 
12.3 
Secondary endpoints 
 
When stated below, baseline is defined as an average of the values collected over the 2 months 
during the run-in period.  Mean baseline laboratory values will be compared to a mean of the 
laboratory values collected at months 8, 10, and 12.  If only one set of data was collected at 
baseline, those data (each a single measurement) will be compared to data collected one year after 
starting/adjusting HU (each a single measurement). 
a. Number of hospitalizations for pain crises and acute chest syndrome as compared to the 1 
year prior to HU initiation or dose increase. 
b. Total hemoglobin level as compared to baseline. 
c. Home analgesic use and comprehensive pain score as compared to before starting or 
adjusting HU. 
d. The percentage of patients that reach MTD. 
e. Quality of life as compared to before starting or adjusting HU. 
f. Markers of organ function (proteinuria, urine osmolality, creatinine, GFR, cystatin C, 
alkaline phosphatase, direct bilirubin, BNP) as compared to baseline. 
g. Ejection fraction and TRV as compared to before starting or adjusting HU. 
h. Overall survival (the percentage of patients who are alive one year after starting/adjusting 
HU). 
i. Transfusion requirement as compared to the 1 year prior to starting or adjusting HU. 
j. 6 minute walk distance and oxygen saturation as compared to before starting or adjusting 
HU. 
k. Concordance of the HU dose as determined by the computer algorithm as compared to the 
manual dose calculated. 
l. Frequency of noncompliance. 


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August 23, 2016 (Amendment O)  
17
m. RBC deformability as related to HbF response to HU 
 
12.4 
Study Analysis 
Primary Response Variable 
The primary response variable is the absolute change of HbF (measured in percentage) from 
baseline to the mean level achieved from months 8, 10, and 12 with algorithm-based HU dosing.  
The baseline of HbF is the mean of the 3 HbF levels measured during the run-in period.  
Descriptive analysis will be performed on the primary outcome variable. Comparison of baseline 
and months 8, 10, and 12 values will be performed using a paired t-test, and a 95% confidence 
interval of the change will be reported.  
 
Secondary Response Variables  
For secondary response variables that are to be compared with their baselines, paired t-test will be 
used for continuous variables (appropriate transformation will be applied where distribution is 
deviated from normal), and McNemar test will be used for categorical variables. For secondary 
response variables that are not being compared with their baselines, descriptive analysis will be 
performed, and mean, standard deviation, 95% confidence interval, and frequencies will be 
calculated, where appropriate.  
 
Model Analysis 
Regression analysis of primary and selected secondary response variables on the following 
factors of interest will be performed: 
1. Final hydroxyurea dose 
2. Hydroxyurea status at baseline  
3. Rate of noncompliance 
4. Number of transfusions 
5. Baseline hemoglobin 
6. Baseline ARC50 
7. Baseline creatinine50 
8. Baseline HbF50 
9. Baseline total bilirubin50 
10. Baseline body mass index50 
11. RBC deformability after starting or increasing HU 
 
Linear Model or Analysis of variance will be the primary method for model analysis in this study. 
The response variables of interest will be regressed as a linear function of the target factors and 
covariates.  
 
Other Issues in Statistical Analysis 
 
Missing values 
Subjects will only be included in the final analyses if data were collected 3 times during the run-in 
period and at months 8, 10, and 12.  For the secondary endpoints where only one set of data were 
collected, analyses of those data will only be performed if data were collected at baseline and after 
one year of therapy.  Subjects with missing measurements will be excluded from the analysis.  
 


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Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
18
12.5 
Stopping Rules 
The study will be monitored to ensure that the occurrence of a specified set of treatment-related 
serious adverse events (TRSAEs) within 24 weeks (+/- 7 days) of the treatment period does not 
substantially exceed an anticipated rate.  The following TRSAEs will be monitored for early 
stopping of the study: 
 
• Death considered to be probably or definitely related to hydroxyurea. 
• Any grade IV toxicity excluding readily reversible metabolic or laboratory abnormalities 
which are considered to be probably or definitely related to hydroxyurea. 
 
The study will be monitored using the stopping rules as outlined below for early stopping if the 
number of subjects in the study who have developed one or more of the above specified TRSAEs 
is over a pre-specified threshold value. TRSAEs are those attributed as definitely or probably 
related to hydroxyurea. From the literature involving long-term follow-up of patients with SCD 
who administer hydroxyurea,14,15 we anticipate the rate of developing at least one of the above 
specified TRSAEs for this patient population to be 10% or less, with estimated SD of about 0.2. 
Following Geller,52 our stopping rule is determined by a Bayesian approach. The stopping 
boundary for the study is reached if the Bayesian posterior probability that the true probability of 
developing one or more of the above specified TRSAEs exceeds this benchmark rate of 10% is at 
least 90%. We take our prior distribution to be a beta distribution with the sum of the two beta 
parameters to be 3, i.e. the parameters of the beta prior distribution are 0.30 and 2.70. These 
parameters are chosen to approximate the prior information about the rate of 0.1 with SD of about 
0.2, with at least 3 patients enrolled before starting the monitoring.  The following table 
summarizes the threshold numbers for stopping the study: 
 
  Number of subjects 
enrolled 
Stop if the number of subjects 
who develop any of the above 
specified TRSAEs reaches: 
≤5 
2 
6-11 
3 
12-18 
4 
19-23 
5 
 
The monitoring plan was evaluated by simulation.  If the true TRSAE rate is 0.1, we will stop about 18% of 
the time.  True TRSAE failure rates of 0.05, 0.15, 0.2 and 0.3 entail stopping about 3%, 41%, 62% and 
91% of the time respectively.     
 
12.6 
Off study criteria 
Patients may withdraw from study at their request.  The risks of withdrawing will be discussed, as 
will alternative treatment options.  During the run-in period subjects may be re-enrolled at their 
request, and at the discretion of the PI.  This will not require re-consenting and subjects may retain 
their original study ID number.  Should any of the following events occur during the 1 year study 
period, hydroxyurea will be discontinued permanently and the subject will be removed from the 
study:  
• Life threatening acute hypersensitivity reaction. 


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Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
19
• Any grade IV toxicity excluding readily reversible metabolic or laboratory abnormalities 
which are considered to be probably or definitely related to hydroxyurea. 
• Pregnancy or unwillingness to use acceptable forms of contraception. 
• More than 2 transfusions per year while on study. 
• HU non-compliance (missing >20% of pills within one month on at least 2 occasions).  
 
Subjects who experience an event referenced above will be followed until resolution of the event.  
Labs will be monitored through 30 days after the final study visit or until he/she recovers to 
baseline, whichever is longer.  
 
Subjects at or near MTD of HU during the run-in period will be taken off study per the discretion 
of the PI.  Alternative treatment options will be discussed with the subject.  
 
All subjects will be followed for 30 days following their last study visit, at which time the 
subject’s participation on this study will be considered complete. Subjects may continue to take 
hydroxyurea after their participation in this study ends. Subjects will then be followed by their 
primary hematologist. 
 
13.0 
DATA AND SAFETY MONITORING PLAN 
 
13.1 
Data and Safety Monitoring  
 
Principal Investigator: Accrual, efficacy, and safety data will be monitored by the principal 
investigator Dr. Courtney Fitzhugh.  The PI, Dr. Matthew Hsieh, and/or Anna Conrey will also 
ensure manually that the HU doses calculated by the computer program are appropriate.   
 
NHLBI’s IRB:  Prior to implementation of this study, the protocol and the proposed patient 
consent and assent forms will be reviewed and approved by the properly constituted Institutional 
Review Board (IRB) operating according to 45 CFR 46. This committee will approve all 
amendments to the protocol or informed consent and conduct continuing annual review so long as 
the protocol is open to accrual or sample and/or data analysis continues.  Accrual and safety data 
will also be monitored and reviewed annually by the IRB. 
 
Quality assurance and control monitoring will be consistent with the NHLBI Division of 
Intramural Research Clinical Research Quality Assurance and Quality Control Policy. 
 
Safety Monitoring/Recording/Reporting of Events: 
 
Serious Events 
Reports to the IRB and CD:   
The PI must report serious UPs, and serious PDs, to the IRB and CD as soon as possible but not 
more than 7 days after the PI first learns of the event. 
 
Reports to the IRB Chair and CD: 
The PI must report all SAEs that do not meet the definition of UP to the IRB chair and CD not 
more than 14 days after the PI first learns of the event.  


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August 23, 2016 (Amendment O)  
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Non-serious Events   
Reports to the IRB and CD: 
The PI must report all UPs that are not serious to the IRB and CD, and PDs that are not serious to 
the IRB, not more than 14 days after the PI first learns of the event. 
 
Deaths 
The PI must report all deaths (that are not UPs) to the CD as soon as possible, but not more than 7 
days after the PI first learns of the event.  
 
Reports at the time of continuing IRB review:  
At continuing review, the PI will provide to the IRB a summary of:   
• All UPs 
• All PDs (except for those granted a waiver of reporting) 
• All AEs (except for those granted a waiver of reporting or any AEs occurred before the 
initiation of the study drugs) 
• If, while preparing the continuing review, the PI identifies a greater frequency or level of 
severity of expected adverse events than was previously identified in the protocol or 
investigational brochure (IB), these should be reported separately as a UP.  If such an 
observation occurs before the time of continuing IRB review, it should be reported to the 
IRB and CD as a UP in the time frames noted above, and summarized at the time of 
continuing review. 
 
We request a waiver from reporting inpatient hospitalization or a prolongation of an existing 
hospitalization for vaso-occlusive pain crisis which, in the opinion of the investigator, is 
attributable to the subject’s sickle cell disease (hospitalization is not uncommon for the subjects in 
this study based on the nature of their illness) to the IRB unless it reaches the threshold of a UP.  
 
13.1.1 Adverse Events: 
Adverse Events (AEs) are defined as any unfavorable and unintended diagnosis, symptom, sign 
(including an abnormal laboratory finding), symptom, or disease which either occurs during the 
study participation, having been absent at baseline or if present at baseline, appears to worsen.  
 
The Principal Investigator will be responsible for assessing AEs. Information on AEs will be 
solicited from subjects through questions from study personnel and information volunteered by the 
subject.  
 
All AEs (serious and non-serious) will be recorded from start of study treatment through final 
study visit and reported to the IRB at the time of continuing review. 
 
All subjects will be expected to experience significant myelosuppression, and only 
myelosuppression that leads to SAEs will be reported to the IRB.  HU is also expected to lead to 
megaloblastic erythropoiesis in all subjects.  Hyperpigmentation and nail discoloration is expected 
to occur in a minority of subjects (<15%) and will only be reported to the IRB if this anticipated 
rate is exceeded.  Further, the GI toxicity described above is expected to occur in a minority of 
subjects (<30%), and will only be reported to the IRB if the GI toxicity leads to an SAE or if the 
anticipated rate is exceeded and not controlled by anti-emetics or by dividing the daily dose of HU 
into 2 portions.   


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Courtney D. Fitzhugh, M.D. 
August 23, 2016 (Amendment O)  
21
 
Suspected adverse reaction: Suspected adverse reaction means any adverse event for which there 
is a reasonable possibility that the drug caused the adverse event. For the purposes of safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between 
the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
 
Unexpected adverse reaction: An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the package insert or is not listed at the specificity or severity that 
has been observed; or is not consistent with the risk information described in the protocol or 
elsewhere in the current application. "Unexpected”, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
 
Adverse events used to evaluate the safety of this protocol regimen will be collected to include any 
unfavorable and unintended signs, symptoms or diseases which either occurs during the study, 
having been absent at baseline or if present at baseline appear to worsen.  The AEs will be 
attributed (unrelated, unlikely, possibly, probably or definitely) to study medication and/or disease 
and graded by severity utilizing CTCAE version 4.0.  A copy of the criteria can be down-loaded 
from the CTEP home page at   http://ctep.cancer.gov/reporting/ctc.html. 
 
Adverse event recording will start after the initial dose of the drug is administered. All AEs, 
including clinically significant abnormal findings on laboratory evaluations, regardless of severity, 
will be followed until satisfactory resolution. AEs should be reported up to 30 days following the 
last study visit.  An abnormal laboratory value will be considered an AE if the laboratory 
abnormality is characterized by any of the following: 
 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms 
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization 
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
 
13.1.2 
Grading of adverse events: 
 
Grade 
 
Category 
Description 
1 
Mild 
Mild; asymptomatic; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL 


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3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL 
4 
Life 
threatening 
Life-threatening consequences; urgent intervention indicated 
5 
Death 
Death related to AE 
 
13.1.3 
Attribution of Adverse Events: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention1 
Unrelated 
The AE is clearly NOT 
related to the intervention 
Unlikely 
The AE is doubtfully related 
to the intervention 
Related to investigational 
agent/intervention1 
Possibly 
The AE may be related to 
the 
intervention 
Probably 
The AE is likely related to 
theintervention 
Definitely 
The AE is clearly related to 
the intervention 
1NOTE: AEs listed as ‘possibly, probably, or definitely’ related to the investigational agent/intervention are 
considered to have a suspected ‘reasonable causal relationship’ to the investigational agent/intervention (ICH E2A). 
 
Serious Adverse Events: 
A Serious Adverse Event (SAE) is defined by federal regulation as any AE that results in any of 
the following outcomes: death, life-threatening AE, requires inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect.   
 
If the serious adverse event is thought to be due to the experimental component of the protocol, 
accession to the protocol may be stopped until a full discussion with the IRB has been held. 
 
Treatment related SAEs (TRSAEs): Those attributed as definitely, or probably, related that will be 
monitored and considered for early stopping of the study according to statistically determined 
criteria.  These include death and any grade IV toxicity considered to be probably or definitely 
related to study medication. 
 
Unanticipated Problems and Protocol Deviations: 
An unanticipated problem is any incident, experience, or outcome that is: 
1. unexpected in terms of nature, severity, or frequency in relation to: 
 
a) the research risks that are described in the IRB-approved research protocol and 
informed consent document, Investigator’s Brochure or other study documents, and 
b) the characteristics of the subject population being studied, and 


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2. related or possibly related to participation in the research, and 
3. places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.  (An AE with a 
serious outcome will be considered increased risk.) 
 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of an IRB-approved research protocol.  Since study drug non-compliance is an expected 
occurrence, we request an exemption from reporting a deviation for less than 20% non-compliance 
in any given month. 
 
Hospitalizations for administrative issues (for example for transfusion) or upgrading to ICU for 
routine monitoring will not be reported as an SAE. 
 
a. Reporting of pregnancy 
Subjects who become pregnant during the study will discontinue the study drug immediately.  The 
investigator, or his/her designee, will collect pregnancy information on any subject who becomes 
pregnant while participating in this study.  An unanticipated problem will be submitted to the Clinical 
Director and the IRB should pregnancy occur during the course of this study. 
 
14.0 
HUMAN SUBJECT PROTECTION 
 
14.1 
Rationale for Subject Selection 
Study population:  The study will be open to all eligible subjects based on inclusion and 
exclusion criteria and who provide informed consent.  No patient will be excluded from 
participation based on gender, race, or ethnicity.  Patients may self-refer, be recruited through the 
NIH office of recruitment, and may include patients participating on NIH Clinical Center 
Protocols and NIH employees and/or children of NIH employees.  If subjects are NIH employees, 
recruitment, enrollment and compensation of NIH employee subjects will be consistent with NIH 
Manual Chapter 23s00-630-3,:”Leave Policy for NIH Employees”. 
 
14.2 
Participation of children 
Hydroxyurea is FDA-approved only for adult patients with SCD.  However, HU has been widely 
used safely in the pediatric population, and multiple clinical trials have been published.28,53-55  
Further, younger patients with SCD are less likely to have evidence of organ damage, and the 
damage that may be present is more likely to be reversible.  Therefore, pediatric patients as young 
as 15 years of age who will be able to understand well the risks of the study including the 
importance of adhering to 2 forms of contraception and benefits of the study will be enrolled. 
 
14.3 
Rationale for the Exclusion of Pregnant Women 
Hydroxyurea can cause fetal harm when administered to a pregnant woman. Hydroxyurea has 
been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, 
hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose 
given on a mg/m2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially 
ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar 
vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a 
mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human 


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24
daily dose on a mg/m2 basis) in rabbits. Women of childbearing potential should be advised to 
avoid becoming pregnant.  Women who are pregnant or lactating are excluded due to the risk to 
the developing fetus or nursing babies. 
 
14.4 
Participation of NIH Staff 
 
• NIH staff may voluntarily participate in this protocol.   
• 
Recruitment, enrollment and compensation of NIH staff subjects will be consistent with the 
Guidelines for the Inclusion of Staff in NIH Intramural Research Studies (December 2015) (SOP 
14F, Appendix C) and NIH Policy Manual Chapter 2300-630-3,:”Leave Policy for NIH Employees 
Participating in NIH Medical Research Studies” 
• If the individual requesting to participate in the protocol is a co-worker, the consent from 
the employee (co-worker) will not be obtained by the research coordinator or the 
employee’s direct supervisor but by another research staff member approved for obtaining 
informed consent. 
• Neither participation nor refusal to participate as a subject in this protocol will have an 
effect, either beneficial or adverse, on the participant’s employment or position at NIH.   
• The consenting staff member will make the NIH Information Sheet on Employee Research 
Participation available to employees who are considering enrolling in research. (SOP 14F, 
Appendix A) 
• Staff subjects’ privacy and confidentiality will be respected by protocol and consenting 
staff the same as for all subjects participating in research protocols. However, all subjects 
will be made aware that there are limits to these protections. 
 
14.5 
Risks and Discomforts  
 
14.5.1 Hydroxyurea 
Toxicities: Toxic effects are primarily bone marrow suppression and rarely gastrointestinal 
disturbances (nausea and vomiting). These effects are dose-dependent and are reversible with 
interrupted therapy. Hydroxyurea is not known to be carcinogenic, although there is a theoretical 
risk of secondary malignancies based upon experience in the myeloproliferative disorders. 
However, no definite predilection to secondary malignancies has been observed despite repeated 
clinical use. There is no proof of increased incidence of leukemia or other malignancies among 
patients enrolled in the randomized polycythemia vera trials or the multi-center HU trials for 
SCD.56,57  
 
Hematologic: Myelosuppression will be expected based on the doses of HU that will be used in 
this study.  Patients’ blood counts will be followed closely, and the doses adjusted as necessary 
per the dosing algorithm.  Patients will also be expected to develop macrocytosis and 
megaloblastic erythropoiesis. 
 
Gastrointestinal Disturbances: Anorexia, nausea, vomiting, diarrhea and constipation have all 
been reported with moderate frequency in patients taking HU. Such disturbances have, rarely, 
been the cause for terminating therapy.  The daily dose will be divided into two portions as 
necessary in order to attempt to improve GI toxicity as described above.  Less frequently, patients 
have experienced stomatitis and rarely pancreatitis.  Concurrent treatment of HU and antiretroviral 


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August 23, 2016 (Amendment O)  
25
agents (including stavudine and didanosine) leads to a higher risk of potentially fatal pancreatitis 
and hepatic failure.  
 
Reproductive: Animal studies suggest that HU may be teratogenic, necessitating caution in 
administering it to females of reproductive age;58 although the number of birth defects does not 
appear to be increased in offspring of women who administered HU during pregnancy.42 HU 
should be used with caution in women of child-bearing age and in men contemplating conceiving 
a child while on this medication.  Subjects will be excluded from the study if they do not agree to 
use two forms of contraception throughout the period of HU administration. 
 
Malignant potential: Long term HU leukemogenesis is extrapolated from myeloproliferative 
disorders. In vitro, there is evidence of copy number changes at specific cytogenetic locations in 
cultured cells. Long term HU therapy is frequently prescribed in polycythemia vera, a condition 
which carries an inherent risk of leukemia. Cases of leukemia have been reported in this 
population; however it is difficult to quantify the leukemogenic potential of HU in this disease.  
There are no studies to date which report an increased risk of malignancy in patients who 
administer HU. 
 
Hyperviscosity: Since HU may increase hemoglobin levels, patients may experience symptoms of 
hyperviscosity.  These symptoms include headache, dizziness, visual impairment, paresthesias, 
muscle weakness, and somnolence.  Phlebotomy will be initiated and/or HU doses will be adjusted 
as above if hemoglobin levels increase to >12g/dL in order to decrease the risk of hyperviscosity.  
 
Other reported side effects: Alopecia, edema, hyperpigmentation, nail atrophy and discoloration, 
rashes, renal disturbances, abnormal transaminases, and neurological symptoms (drowsiness, 
dizziness, disorientation, hallucinations, seizure, peripheral neuropathy and headache) have all 
been reported infrequently.  Acute diffuse pulmonary infiltrates and pulmonary fibrosis have been 
reported rarely. 
 
14.5.2 Phlebotomy and blood draws 
The inconvenience and discomfort associated with phlebotomy relate to the intravenous catheter 
placement and blood removal.  The risks associated with intravenous catheter placement include 
brief but relatively minor pain, bleeding, localized tissue damage, bruising, and induction of a 
small clot in a superficial blood vessel.  If patients have permanent access devices such as a 
mediport, the permanent catheter will be used if possible.  Risks associated with phlebotomy 
and/or blood draws include symptoms related to a fear of blood drawing, temporary lowering of 
blood pressure, dizziness, lightheadedness, fainting, and rarely seizures.  Patients will be 
encouraged to drink plenty of fluids prior to phlebotomy, and intravenous fluids will be 
administered as necessary. 
 
14.5.3 Quality of life questionnaire and pain diary 
The only anticipated adverse consequences associated with the quality of life questionnaires and 
pain diaries will be the time required for the participants to complete each questionnaire and pain 
diary. 
14.5.4 Echocardiogram 
There are no known adverse consequences related to the ultrasound waves. 
 


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14.6 
Risks in Relation to Benefits 
For adult participants: 
Risk/Benefit Analysis: 
The benefits to the patients include potentially decreasing the frequency of some of the acute 
complications associated with sickle cell disease and improving quality of life as well as possibly 
preventing or decreasing organ dysfunction and improving survival.  Potentially, transfusions and 
hospitalizations could also be avoided or postponed.  Further, the knowledge gained should help 
contribute to the design of future trials.  Therefore, this research involves greater than minimal risk 
to subjects with the prospect of direct benefit (45 CFR 46.102). 
 
For pediatric participants aged 15-18: 
The inclusion of children satisfies the criteria set forth in 45 Code of Federal Regulations 46, 
Subpart D as follows: 
 
(a) the risk is justified by the anticipated benefit to the subjects: 
 
Trials involving pediatric patients have also shown a decrease in the frequency of some of the 
acute complications associated with sickle cell disease, and this will likely lead to an improvement 
in quality of life.  Further, enrolling patients at a young age before significant organ damage 
occurs may help to prevent the development of organ damage and potentially improve survival.   
Potentially, transfusions and hospitalizations could also be avoided or postponed.   
 
(b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that 
presented by available alternative approaches: 
 
The alternatives are hydroxyurea dosing by a primary provider which may not lead to an optimal 
fetal hemoglobin response, no sickle-specific therapy and treating acute complications 
conservatively with hospitalization as necessary, or transfusion therapy with the associated risks of 
alloimmunization, hemolytic transfusion reaction, and iron overload; and 
 
(c) adequate provisions are made for soliciting the assent of the children and permission of their 
parents or guardians, as set forth in 46.408. 
 
Therefore for children participating in this study, the risk is consistent with 45 CFR 46.405, 
Children’s risk category Assignment 2:  the research involves greater than minimal risk but 
presents the prospect of direct benefit to the individual subjects. 
 
14.7 
Informed Consent Processes and Procedures 
All subjects will read and sign the informed consent document prior to enrollment.  Members of 
the protocol team will describe the protocol and the risks and benefits of each to the individual 
signing the consent.  The principal investigator or the associate investigators designated to obtain 
informed consent may consent the research subject and sign the consent documents after the case 
has been discussed with the PI and/or the primary clinical team.   
 
If the subject is a minor, the parent who signs the consent for the minor must be a legally 
recognized parent or guardian.  The child will also be included in all discussions about the trial 
and a minor's assent will be obtained.   The parent or guardian will sign on the designated line on 


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August 23, 2016 (Amendment O)  
27
the informed consent attesting to the fact that the child had given assent.  We will inform the 
minor during the assent process that for safety, we need to do a pregnancy test.  She will also be 
told that if it is positive, we will counsel her and help her tell her parents.  If the minor does not 
want to proceed she will be advised not to sign the assent and her enrollment on this protocol will 
end. 
 
When a pediatric subject reaches age 18, continued participation will require re-consenting of the 
now adult with the standard protocol consent document to ensure legally effective informed 
consent has been obtained. Should sample or data analysis continue following completion of active 
participation and the subject has reached 18 years of age, we will attempt to contact the subject 
using the last known contact information to obtain consent for continued use of data or samples  
collected during their prior visit. Given the length of time that may have transpired for some of the 
subjects since their last visit for this study, we request waiver of informed consent for those 
individuals who after good faith efforts to contact them, we are unable to contact. 
 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d), each of which must be 
addressed in relation to the protocol: 
 
(1) The research involves no more than minimal risk to the subjects; 
a) Analysis of samples and data from this study  involves no additional risks to subjects. 
(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects; 
a) Samples and data will be kept in secure locations in the laboratory of Dr. Young. Retention 
of samples or data does not affect the welfare of subjects. 
(3) The research could not practicably be carried out without the waiver or alteration; and 
a) Considering the length of time between a minor’s enrollment and their age of majority, it is 
possible that more than a few subjects may be lost to follow up.  A significant reduction in 
the number of samples analyzed could impact the quality of the research. 
(4) Whenever appropriate, the subjects will be provided with additional pertinent information after 
participation. 
a) We only plan to request a waiver of re-consent for those subjects who have been lost to 
follow-up. 
 
If the individual obtaining consent is a supervisor of the employee requesting to participate in the 
protocol, there will be independent monitoring of the consent process to minimize the risk of 
undue pressure on the employee.  If the individual requesting to participate in the protocol is a co-
worker, there will be independent monitoring of the consent process unless this is waived by the 
IRB.  Independent monitoring will be provided by the Clinical Center Department of Bioethics 
Consultation Service. 
 
If at any time during participation in the protocol, new information becomes available relating to 
risks, adverse events, or toxicities, this information will be provided orally or in writing to each 
enrolled or prospective patient.  Documentation will be provided to the IRB and if necessary the 
informed consent amended to reflect relevant information. 
 
Informed Consent of Non-English Speaking Research Participants: 
If there is an enrollment of a research participant for which there is no translated extant IRB 
approved consent document,  the principal investigator and or those authorized to obtain informed 


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consent will use the Short Form Oral Consent Process as described in MAS Policy M77-2, 45 
CFR 46.117 ( b) (2). The summary that will be used is the English version of the extant IRB 
approved consent document.   
 
We request prospective IRB approval of the use of the short form for up to a maximum of five 
participants and we will notify the IRB at the time of continuing review of the frequency of the use 
of the Short Form.  Should we reach the threshold of five, we will notify the IRB of the need for 
an additional use of the Short Form and that we will have the consent document translated into the 
given inherent language. 
 
Exclusion of participants unable to provide informed consent: 
All participants must be capable of providing informed consent.  Participants not capable of 
providing informed consent, needing a legally authorized representative, will be excluded from 
participating in this study.  The rationale for exclusion is while there may be direct benefit from 
participation, this is a pilot study with greater than minimal risk and this justifies requiring that 
each participant be able to provide informed consent. 
 
14.8 
Conflict of Interest 
The Principal Investigator assured that each associate investigator listed on the protocol title page 
received a copy of the NIH’s Guide to preventing conflict of interest.  No initial or subsequent 
members of the research team reported a potential conflict of interest. 
 
15.0 
PHARMACEUTICALS  
 
15.1 
Hydroxyurea 
Names:  
Hydroxyurea, Hydrea, Droxia® 
 
Supply:  
Commercially available 
 
Product description:  
Hydroxyurea is available for oral use as capsules providing 200 mg, 300 mg, and 500 mg of 
hydroxyurea. The 200 mg, 300 mg, and 500 mg capsules are stocked by the NIH Clinical Center 
Pharmacy.  
 
Storage and stability:  
Oral capsules should be stored at controlled room temperature 15-30ºC (59-86ºF).  
 
Route of administration:  
Oral administration.  
 
Regulatory Status:  
OFF Label Usage   
 
Hydroxyurea will be used in this study beyond what is indicated in the package insert.  Hydroxyurea is 
approved by the FDA to prevent pain crises in adults with SCD; however this protocol will enroll subjects 


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29
as young as 15 years old.  The use of this drug meets the requirements for an exemption from the 
IND regulations, 21 CFR 312, specifically:    
 
1. The investigational drug is lawfully marketed in the United States 
2. The investigation is not intended to be reported to the FDA as a well-controlled study in 
support of a new indication for use of the drug product 
3. The investigation is not intended to support a significant change in advertising to an 
existing lawfully marketed prescription drug product 
4. The investigation does not involve a route of administration or dosage level or use in a 
patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product. 
5. The investigation will be conducted in compliance with the requirements for institutional 
review set forth in FDA regulations 21 CFR 56, and requirements for informed consent as 
set forth in FDA regulations 21 CFR 50 
6. The investigation will be conducted in compliance with FDA regulations 21 CFR 312.7:  
Promotion and charging for investigational drugs. 
 
 
Advice to Patients:  
 
Hydroxyurea is a medication that must be handled with care.  People who are not taking 
hydroxyurea should not be exposed to it.  If a caregiver must handle the medication for you, hands 
must be washed after handling.  If the powder from the capsule is spilled, it should be wiped up 
immediately with a damp disposable towel and discarded in a closed container, such as a plastic 
bag. The medication should be kept away from children and pets. Women of childbearing 
potential will be advised to avoid becoming pregnant.  


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16.0 
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31
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August 23, 2016 (Amendment O)  
32
34. 
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38. 
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from the BABY HUG trial. Pediatric blood & cancer. Feb 2010;54(2):260-264. 
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APPENDIX A: NIH INFORMATION SHEET ON STAFF RESEARCH PARTICIPATION 
 (DECEMBER 2015) 
As an NIH employee, contractor, Special Volunteer, Guest Researcher, or trainee, you may participate in 
intramural research studies unless it is prohibited by your Institute or Center (IC), or if you are excluded by 
the criteria of the protocol in which you want to enroll. The inclusion of NIH staff in a particular protocol 
must also be approved by the IRB. You may be motivated by altruism, a commitment to research in your 
own or related fields, or want access to clinical trials of potential direct therapeutic benefit. 
When deciding, you should make an informed decision about participation. This information sheet offers 
some points to consider for NIH staff who are considering research participation at NIH. 
 
First, similar to any individual who is considering research participation, you should seek adequate 
information about the study purpose, what is required of you in terms of procedures, interventions and time, 
and the potential risks and benefits of participation. For more information, see the NIH Clinical Center’s 
public website “Are Clinical Studies for You?” at http://www.cc.nih.gov/participate/studies.shtml. 
 
When you are thinking about participation in a research study that is being conducted by your supervisor, 
or others with whom you work closely in your laboratory, branch, or unit, you should consider some 
additional factors: 
 
A. Possible bias: Are you confident that you can be unbiased about reporting answers, side effects, or other 
information that could influence the study outcome or risk to you? 
 
B. Confidentiality: Are you comfortable sharing your medical history (including, for example, mental 
health history or STDs) and your social history (e.g. substance use) with study investigators who may be 
your coworkers, or with the possibility of them discovering something about your health during the study 
(e.g. pregnancy status or a new diagnosis)? Although every effort will be made to protect your information 
and keep it private and confidential, your information will be available in medical records and it will be 
available to authorized users outside of the study team, both in an identifiable and unidentified manner. 
 
C. Pressure: Do you perceive any pressure or expectations from your supervisor or colleagues regarding 
participation? Could that pressure influence your decision or make it difficult for you to choose whether or 
not to participate? Remember that it is your choice whether or not to participate and that your decision to 
participate or not should not have an effect, either beneficial or adverse, on your position at NIH. 
 
D. Time and Compensation: Can you take time off from work to complete the study requirements or 
participate solely during non-duty hours? Can you receive compensation for your participation in this 
study? Will your supervisor give you permission to participate during work hours? See the NIH Policy 
Manual 2300- 630-3 Leave Policy for NIH Employees Participating in NIH Medical Research Studies. 
 
E. Consent Process: Is the person obtaining your consent for the study your supervisor, a subordinate, or 
co-worker? If so, is there an independent person monitoring the consent process? If the study PI is a 
supervisor and intends to obtain consent from you, an independent person (e.g., through Bioethics or the 
NIMH Human Subjects Protections Unit [HSPU], or others as approved by the IRB) must monitor the 
consent process. If the person obtaining consent from you is a co-worker then an independent person (e.g., 
through Bioethics or the NIMH HSPU, or others as approved by the IRB) may be required to monitor the 
consent process, as determined by the IRB for the specific study. 
 
If you are thinking of enrolling as a subject at the NIH Clinical Center and you have any questions or 
concerns, please contact the Office of Human Subjects Research Protections (OHSRP) at 301-402-3444 
and/ or the Patient Representative if you are thinking of enrolling as a subject at the NIH Clinical Center on 
301-496-2626. If you are at a NIH site outside the Clinical Center then please contact local site leadership.