out.pdf

Page 1/20

Hydroxyurea Optimization through Precision Study
(HOPS): study protocol for a randomized,
multicenter trial in children with sickle cell anemia
Emily R. Meier 

Indiana Hemophilia and Thrombosis Center
Susan E. Creary 

Nationwide Children’s Hospital
Matthew M. Heeney 

Boston Children’s Hospital
Min Dong 

Cincinnati Children’s Hospital Medical Center
Abena O Appiah‐Kubi 

Cohen Children’s Medical Center
Stephen C. Nelson 

Children’s Hospital and Clinics of Minnesota
Omar Niss 

Cincinnati Children’s Hospital Medical Center
Connie Piccone 

Case Western Reserve University School of Medicine
Maa-Ohui Quarmyne 

Children’s Healthcare of Atlanta
Charles T. Quinn 

Cincinnati Children’s Hospital Medical Center
Kay L. Saving 

University of Illinois Peoria
John P. Scott 

Medical College of Wisconsin
Ravi Talati 

Cleveland Clinic Children’s Hospital
Teresa S. Latham 

Cincinnati Children’s Hospital Medical Center
Amanda Pfeiffer 

Cincinnati Children’s Hospital Medical Center
Lisa M. Shook 

https://doi.org/10.21203/rs.3.rs-33650/v2

Page 2/20

Cincinnati Children’s Hospital Medical Center
Alexander A. Vinks 

Cincinnati Children’s Hospital Medical Center
Adam Lane 

Cincinnati Children’s Hospital Medical Center
Patrick McGann  (  [email protected] )

Cincinnati Children’s Hospital Medical Center https://orcid.org/0000-0001-6198-4785

Study protocol

Keywords: Sickle cell anemia, pharmacokinetics, hydroxyurea, pediatrics

DOI: https://doi.org/10.21203/rs.3.rs-33650/v2

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.  
Read Full License

mailto:[email protected]

https://orcid.org/0000-0001-6198-4785

https://doi.org/10.21203/rs.3.rs-33650/v2

https://creativecommons.org/licenses/by/4.0/

Page 3/20

Abstract
Background : Sickle cell disease (SCD) is a severe and devastating hematological dis that affects
over 100,000 persons in the United States and millions worldwide. Hydroxyurea is the primary disease-
modifying therapy for the SCD, with proven bene�ts to reduce both short-term and long-term
complications. Despite the well-described inter-patient variability in pharmacokinetics (PK),
pharmacodynamics and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a
subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose
escalation process is time consuming and requires frequent laboratory checks, many providers default to
a �xed dose, resulting in inadequate hydroxyurea exposure and suboptimal bene�ts for many
patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children
with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides
superior clinical and laboratory bene�ts than traditional dosing strategies. However, it is not clear whether
these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in
the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the
feasibility and bene�ts of this PK-guided dosing approach in a multi-center trial.  

Methods : HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children
with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited
from 11 pediatric sickle cell centers across the United States, are randomized to receive hydroxyurea
either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK
data will be collected using a novel sparse microsampling approach requiring only 10μL of blood
collected at 3 time-points over 3 hours. A protocol-guided strategy more aggressive protocols is then used
to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary
endpoint is the mean %HbF after 6 months of hydroxyurea. 

Discussion:  HOPS will answer important questions about the clinical feasibility, bene�ts, and safety of
PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm
from a standard weight-based approach to one that safely and effectively optimize the laboratory and
clinical response. 

Trial registration: ClinicalTrials.gov, NCT03789591. Registered on December 28, 2018.

Background
Sickle cell disease (SCD) is a devastating, inherited dis of hemoglobin, affecting over 100,000
persons in the United States and millions worldwide.1-3 The most severe forms of SCD, primarily HbSS
and HbS/β0-thalassemia, account for a majority of the global cases of SCD and are collectively referred
to as sickle cell anemia (SCA). Without early diagnosis and appropriate disease-modifying treatment, SCA
results in signi�cant morbidity and early mortality. The life-threatening clinical complications of SCA,
including acute splenic sequestration crisis and stroke, frequently occur within the �rst decade of life.4,5

Page 4/20

Organ damage caused by recurrent vaso-occlusion and tissue ischemia, which is often clinically silent,
begins as early as 4-6 months of age, when fetal hemoglobin (HbF) begins to decline and sickle
hemoglobin (HbS) starts to predominate.6-8 Hydroxyurea has emerged as the primary disease-modifying
therapy for SCA9 with decades of evidence demonstrating the salutary laboratory and clinical effects,
including reduction in both morbidity10-12 and mortality.13-16 The bene�ts of hydroxyurea are primarily
due to its ability to increase the production of HbF.9,17 In response to a growing body of evidence
demonstrating the bene�ts and safety of hydroxyurea, highlighted by the randomized, double-blind,
placebo-controlled phase III BABY HUG trial, the National Heart, Lung, and Blood Institute (NHLBI)
published guidelines in 2014 recommended that hydroxyurea be offered to all infants with SCA starting
at 9 months of age, regardless of clinical severity.18 For pediatric sickle cell centers that have
successfully initiated hydroxyurea in infants and young children, there has been a notable improvement
in the health of these children.19 While the 2014 guidelines increased the early initiation of hydroxyurea,
use remains concerningly low with recent data suggesting that less than 50% of children with SCA are
prescribed this life-saving medication.20,21

In addition to the importance of early initiation of hydroxyurea to prevent SCA complications, our
experience documents that hydroxyurea dosing is also a critically important determinant to optimize the
clinical and laboratory effects of the medication. The clinical bene�ts of hydroxyurea are maximized
when the HbF production is optimized and HbF effect is largely determined by degree of hydroxyurea
exposure.22 Even with modest HbF induction at lower doses, most patients have some clinical or
laboratory bene�ts. However, optimal dosing is highly variable from patient to patient due to signi�cant
inter-patient variability in drug pharmacokinetics (PK) and pharmacodynamics (PD).23-26 Optimal doses
range from 15-35 mg/kg/day, resulting in many patients receiving less than 50% their personalized, ideal
dose. Recognizing this variability and using a precision medicine approach, we developed a model to
individualize hydroxyurea dosing and optimize hydroxyurea response with the goal of minimizing the
short- and long-term complications of SCA in young patients. With traditional hydroxyurea dosing, HbF
levels ≥15-20% are considered a therapeutic success as they are often associated with a reduction in (but
not elimination of) many clinical complications of SCA. A model-based publication suggests that HbF
levels greater than 30% can achieve a “pharmacologic cure of most disease manifestations.”27,28 In the
Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154), we
demonstrated that an individualized, PK-guided dosing strategy resulted in a more robust HbF response
than seen with traditional weight-based dosing, as enrolled children achieved 30-50% HbF levels and had
an absence of clinical SCA symptoms when initiating hydroxyurea at a PK-guided starting dose.29 These
unprecedented results in a population including children and young adults (6 months-21 years of age)
have led to the hypothesis that early initiation and optimized hydroxyurea dosing actually can prevent,
rather than only ameliorate, most short- and long-term sickle cell complications, including health-related
quality of life.

Although encouraging, TREAT was a single-arm study at a single institution and many questions still
remain. The TREAT cohort was very young in age with most children starting in the �rst 1-2 years of life 

Page 5/20

while HbF levels remain high, it is not clear whether the robust HbF response observed was due to the
early initiation of hydroxyurea (before genes involved in HbF expression may be fully silenced), whether
this was a result of PK-guided dosing, aggressive dose escalation strategies, or perhaps a combination of
the three. In addition, the ability to measure hydroxyurea concentrations is not widely available and the
hydroxyurea PK model and PK-guided dosing strategy has not been used outside of Cincinnati Children’s
Hospital Medical Center (CCHMC). Finally, the feasibility of performing PK studies in this population in
the clinical setting including laboratory studies that require shipment of temperature-sensitive samples,
and timely determination and implementation of a PK-guided hydroxyurea dosing regimen are important
questions to answer to successfully implement personalized medicine approaches, such as this, among
children with SCA in clinical practice. The Hydroxyurea Optimization through Precision Study (HOPS) is
designed to address these speci�c key operational components. The multicenter trial includes several
novel and innovative features, including individualized hydroxyurea dosing, sparse PK sampling requiring
very small volumes of blood, a novel method of measuring hydroxyurea concentrations, and centralized
initial dose selection with in a prospective, multicenter randomized trial.

Methods/design
Trial design

HOPS is a prospective, multicenter, randomized trial that aims to evaluate whether initial dosing of
hydroxyurea using a novel PK-guided dosing strategy for children with SCA results in higher %HbF at 6
months compared to standard weight-based initial dosing with step-wise dose escalation. The
multicenter design also allows for the validation of PK sample collection in young children with
centralized PK analysis and dose selection. Participants are randomized in a 1:1 ratio to initially receive
either a 20 mg/kg weight-based (Standard Arm) or a PK-guided (Alternative Arm) starting dose of
hydroxyurea. Following initiation, a study-designed hydroxyurea dosing protocol will be used to escalate
or reduce the initial hydroxyurea dose based on the laboratory data that will be collected through the time
of the primary endpoint at month 6; the total study period is 12 months. Figure 1 outlines the schedule of
events for participants in the study.

Objectives

The primary objective of the study is to evaluate whether a PK-guided starting hydroxyurea dose results in
a higher %HbF compared to standard weight-based (20 mg/kg) initial dosing for children with SCA.
Secondary aims include careful investigation of the clinical, laboratory, and molecular determinants of
the maximal hydroxyurea-induced HbF responses, as well as studies investigating changes in gene
expression and regulation related to hydroxyurea starting dose and age.

Study settings

Study participants are recruited from 11 pediatric sickle cell centers across the United States (Figure 2).
Most study sites were selected due to their involvement in the Sickle Treatment and Outcomes Research

Page 6/20

in the Midwest (STORM) regional network, led by CCHMC and established to improve care and outcomes
for individuals with SCD living in Indiana, Illinois, Michigan, Minnesota, North Dakota, Ohio, South Dakota,
and Wisconsin.30 Additional study sites were included to ensure adequate enrollment and were selected
based on previous collaborative relationships and investigator interest. Prior to the initiation of the study,
there was signi�cant variability in the number of patients (30 to greater than 500) and the proportion of
children prescribed hydroxyurea (25-90%) at each site, mimicking the distribution of these patients across
the United States and the known variability in hydroxyurea utilization. Prior to formal site selection,
potential study sites completed a feasibility survey to assess patient volume, current hydroxyurea use,
research capacity, and anticipated study enrollment. Subsequently, an in-person or virtual site
training/initiation visit was performed, including review of study rationale and procedures as well as a
comprehensive overview on the use of hydroxyurea therapy and sharing of the results from the TREAT
trial. These site visits were well-received and allowed each study team to understand the rationale and
strategy for dosing in the HOPS trial, which was different than the previous dosing strategies used for
patients with SCA at these centers. Potential barriers to the recruitment of study participants or to the
performance of study-related procedures were also reviewed to optimize the chance of smooth study
success at each site.

Eligibility criteria

Children with con�rmed SCA (HbSS, HbSD, Hbβ0-thalassemia or other similarly severe phenotypes) who
are initiating hydroxyurea therapy, following a discussion with their local clinical team, are eligible for
study consideration. As each of these SCA genotypes is considered to have a similar phenotype and
because we expect most enrolled participants to have HbSS disease, there will be no attempts to balance
distribution of genotypes across the two study arms.

Inclusion Criteria:

1. Diagnosis of SCA (HbSS, HbSD, HbS/β0-thalassemia, or similarly severe SCA genotype)

2. Age 6 months to 21 years at the time of enrollment

3. Clinical decision by patient, family, and healthcare providers to initiate hydroxyurea therapy

Exclusion criteria:

1. Current treatment with chronic, monthly blood transfusions or erythrocytapheresis. Of note, there are
no restrictions regarding enrollment as to recent single blood transfusions. HbF is calculated as
HbF/(HbF+HbS) to account for the presence of HbA. Children who are transitioning from chronic
transfusions to hydroxyurea therapy are not eligible due to the di�culty in evaluating response with
the overlap period of simultaneous transfusion therapy and hydroxyurea.

2. Treatment with hydroxyurea within the past 3 months

3. Hemoglobin SC disease, HbS/β+-thalassemia

4. Current treatment with other investigational sickle cell medications

Page 7/20

Recruitment and Enrollment Procedures

The study recruits patients who have decided to initiate hydroxyurea therapy based upon clinical
indications and shared decision-making between the providers and the family. Informed consent is
obtained by investigators or local research personnel at each study site. For children under 18 years of
age, the parent or legal guardian provides written informed consent to join the study at the time of
enrollment and older children sign assent as required by their local IRB. Participants who are 18 years and
older sign informed consent themselves.  In addition to informed consent to participate in the trial,
additional consent is obtained for the storage of biological specimens for subsequent analysis.

Pharmacokinetics Studies and Determination of Hydroxyurea Dose

Once informed consent is obtained, all participants have a baseline PK visit. At this visit, participants take
a single 20 mg/kg dose of liquid hydroxyurea prepared at each study site and PK microsamples are
collected at 3 time points (15 minutes, 60 minutes, and 180 minutes) as described below. The liquid
formulation is used for the PK studies to allow for a precise 20 mg/kg dose, but older participants are
allowed to take capsules if they choose once hydroxyurea is prescribed. After the baseline visit, the
participant does not start hydroxyurea until a study-determined starting dose is established and
prescribed by their local provider, typically within 1-2 weeks of the PK visit. PK samples are shipped on dry
ice to the central laboratory at CCHMC for measurement of hydroxyurea concentrations, determination of
PK curve and area under the concentration-time curve (AUC), calculation of starting dose options for both
arms, and randomization. Randomization results are blinded to the PI and staff involved in the
recruitment and management of study participants until the study is complete.

Below, we describe several novel features of the study, including sparse PK sampling using
microsampling devices, novel methods of measuring hydroxyurea concentrations, and determination of
the optimal PK-guided dose for each individual participant.

Sparse PK Sampling

Traditional PK sampling requires collection of 1-3 mL of venous blood at many time points over several
drug half-lives. This collection frequency and relatively large-volume venous blood draws over 8-12 hours
is not practical in a clinical setting, particularly for infants and young children, notably the di�culties and
intolerance of frequent venous blood draws in very young children and the inconvenience of having to
remain in the hospital/clinic setting for a long period of time. Through the TREAT study, using historical
data,23 we developed a population PK model and a sparse sampling strategy that accurately estimates
hydroxyurea drug exposure using only three hydroxyurea concentrations measured at optimally designed
times: 15 minutes, 60 minutes, and 3 hours after hydroxyurea administration.31 The number and timing
of sample collection was selected based on known PK patters such that an accurate estimation of
exposure could be made. Additionally, as we hope for this PK-guided dosing strategy to be ultimately
clinically feasible, we found that the collection of 3 samples over 3 hours was acceptable to both families
and feasible within a clinical setting. The TREAT cohort demonstrated the feasibility and safety of this

Page 8/20

sampling strategy in young children and older adolescent/young adults at a single center.29 The PK
sampling strategy was an important feature of TREAT that resulted in high rates of enrollment with >90%
of children with SCA who initiated hydroxyurea during the study period agreeing to participate.

Microsampling and Measurement of Hydroxyurea Concentrations

There is no widely established method or commercially available technique for measuring hydroxyurea
concentrations in biological samples, but several new and accurate techniques have been developed.32

Our novel HPLC-based assay, requiring 0.5-1.0 mL of blood per time point, was the primary assay used in
the TREAT study,29 and was a signi�cant improvement from the previously used colorimetric assay,which
required 1-2 mL per time point.33,34 We have since miniaturized the hydroxyurea assay further through the
development of a highly sensitive and accurate tandem mass spectrometry-based assay (LC-MS/MS) for
the quantitative measurement of hydroxyurea, requiring even smaller volumes of blood.35 Blood
collection occurs using novel Volumetric Absorption Microsampling (VAMS) devices (Neoteryx, LLC,
Torrance, CA), which store exactly 10 µL and samples can be collected by �nger stick or heel stick, which
is much preferred compared to venous sampling, for young children.  Figure 3 illustrates the
microsampling collection process using these VAMS devices.

To validate this novel PK microsampling method, we compared hydroxyurea concentrations and AUC
measurements using the established HPLC assay to the new LC-MS/MS assay. Among 80 samples from
23 TREAT participants, both methods gave simlar hydroxyurea concentrations and AUC measurements
(Figure 4A and 4B, r>0.90 for both comparisons). Importantly, this strong correlation in individual
hydroxyurea concentrations also resulted in very similar recommended doses to target the desired AUC.
PK-guided doses were calculated using data from both methods and demonstrated similar doses with a
mean difference of -1.7 ± 2.6 mg/kg in comparing the two methods. As hydroxyurea concentrations (and
thus calculated AUC) tended to be slightly higher as measured by LC-MS/MS than HPLC, there were no
recommended doses calculated using LC-MS/MS values that were greater than 3 mg/kg from the HPLC
calculated dose. These data, and the ease of collecting low volume samples using this technique
provided con�dence to use this technique as the primary method of hydroxyurea  measurement for the
HOPS trial.

For HOPS, PK samples are collected in duplicate using the described sparse sampling strategy (samples
collected at 15 minutes, 60 minutes, and 180 minutes following the hydroxyurea dose) and the VAMS
devices as shown in Figure 3.

Determination of PK-guided dose

As was done in the TREAT study, hydroxyurea concentrations are incorporated into the previously
described population PK-model using MW/Pharm (Mediware, Prague, Czech Republic).36 To determine
the PK-guided dose, each participant’s absorption pro�le is used to determine the dose that would achieve
target AUC of 115 mg*h/L. This AUC target was determined through the analysis of PK studies performed

Page 9/20

in a cohort of children with SCA from the Hydroxyurea Study of Long-term Effects (HUSTLE,
NCT00305175) after they reached a clinically-determined maximum tolerated dose.23,31 The optimal PK-
guided dose is calculated and recorded for all participants, but only those participants randomized to the
Alternative Arm would initiate hydroxyurea at this dose. At the conclusion of the study, the PK-guided
dose calculated for the Standard Arm will be compared to the dose achieved through the dose escalation
process. The PK-model allows for determination of a speci�c dose (in mg) that approximates an AUC of
115 mg*h/L, but at times this dose is not convenient using common dosage forms (100 mg/mL liquid or
500 mg capsules). For participants who choose to take liquid hydroxyurea, the recommended starting
doses (for both arms) are rounded to the nearest 20 mg (0.2mL). For older participants who choose to
take hydroxyurea capsules, a daily dose is selected that best approximates the recommended dose. This
at times requires different doses on different days. For example, if a dose of 750 mg is recommended, the
participant would alternate taking one (500 mg) and two (1000 mg) capsules each day for an average
daily dose of 750 mg. Hydroxyurea will only be started if there are no baseline cytopenias as de�ned in
the toxicity criteria in Table 1.

Randomization and blinding

Participants who complete their baseline PK visit are randomized in a 1:1 ratio to receive either
hydroxyurea using a starting dose of 20 mg/kg/day (Standard Arm) or an individualized, PK-guided dose
(Alternative Arm). All participants have both a standard (20 mg/kg) and PK-guided starting dose
calculated and entered into a locked Research Electronic Data Capture (REDCap) form visible only to
select members of the Data Coordinating Center, after which randomization occurs. The random
allocation sequence is generated using the REDCap randomization module. The randomization procedure
is strati�ed by age (age< 2 and age>2 years). This strati�cation for age is performed to increase the
likelihood of having age balance in each treatment arm due to the fact that the primary endpoint (%HbF)
is typically higher in children less than 2 years than in older children.6 In the current era, guided by the
2014 NHLBI guidelines, most children with SCA are at least offered hydroxyurea and many begin taking
hydroxyurea at a young age. We thus anticipate that the enrollment age for HOPS will be young, though
likely not quite as young as the TREAT cohort given that there simply are not many older patients who
have not yet been offered or started on hydroxyurea. The strati�cation for age is included to ensure each
arm is balanced in terms of older and younger participants. Randomization is performed using a
truncated binomial rule with permuted blocks, each 4 in size, within each stratum. The probability of
assigning either treatment within each permuted block will be ½, until one of the two treatments has been
assigned twice; all subsequent patients within the block receive the remaining treatment. This ensures
that within each block as well as at the end of the study the treatment assignment is balanced. The Data
Coordinating Center manager and REDCap data specialist, who are not involved in participant screening,
enrollment, or assessment, are the only people with knowledge of the study arm. At this time, the local
study team is informed that randomization has occurred and starting dose is available. The starting dose
is provided as an absolute (mg) dose and entered into the REDCap study database.

Page 10/20

The study is designed with the intent of a double-blind design, but is not formally labeled a “double-blind”
trial due to the fact that hydroxyurea is used as an open-label study medication and the study team will
know if the mg/kg dose is notably different than 20 mg/kg. Despite this possibility, the study arm is not
explicitly provided to the provider or the family, and the same procedures are used for dose escalation or
reduction throughout the remainder of the study. Additionally, because there are some patients on the
Alternative (PK-guided)  Arm who may have a dose that is very close to or the same as the Standard Arm
dose of 20 mg/kg dose, it is not always possible to know the study arm assignment. Accordingly, we do
not anticipate that lack of formal blinding will create bias in the treatment or outcomes of enrolled
participants.

Study-directed Hydroxyurea Dosing

The primary objective of HOPS is to compare PK-guided dosing to traditional, weight-based dosing. After
selection of the starting dose, all participants, regardless of starting dose, are monitored and have dosage
adjusted in the same way. The dose may be adjusted every 8 weeks based on laboratory values to target
moderate myelosuppression. The maximum daily dose of hydroxyurea on the HOPS protocol will not
exceed 35 mg/kg/day. The dose adjustment and toxicity criteria (Table 1) were decided upon through a
consensus of study investigators and are less conservative than are used by most centers or previously
published settings, tolerating lower absolute neutrophil, absolute reticulocyte, and platelet counts to
optimize clinical bene�ts while still maintaining patient safety. This consensus decision was based on
clinical experience that severe myelosuppression, even with the higher doses used in the TREAT trial, are
uncommon with hydroxyurea therapy. With each study visit, participants’ prescribed dose and laboratory
values are reviewed by their clinical provider who determines one of four options: 1) continue to prescribe
hydroxyurea at the same dose, 2) escalate the prescribed dose, 3) adjust the prescribed dose to account
for weight gain, or 4) temporarily hold and/or decrease the prescribed dose. Table 1 summarizes the dose
adjustment and toxicity criteria. The study also created a HOPS Dosing Calculator, available on the study
website to assist prescribers and to reduce the potential for variation in dosing regimens across study
sites (Figure 5). While the calculator is designed to guide dosing decisions, dosing decisions can rely
upon clinical discretion at any time throughout the study.Medication adherence is encouraged and
patients/caregivers self-report their adherence in person at study visits, by telephone, or if the family
agrees, through an electronic REDCap survey sent automatically on a monthly basis by text message or e-
mail. We recognize that suboptimal adherence is the primary barrier to effective hydroxyurea therapy, but
we aim for this study to mimic “real-world” circumstances and purposefully did not include excessive
efforts to address medication adherence.

Outcome Measures

The primary endpoint is the mean %HbF at 6 months, and participants who are randomized to either the
Standard or Alternative Arm are included in the primary endpoint analysis according to the intent to treat
principle. We hypothesize that the %HbF will be at least 5 percentage points higher (e.g. HbF of 25%
compared to HbF of 30%) in children who initiate hydroxyurea at the PK-guided dose compared to those

Page 11/20

who start at a standard, 20 mg/kg dose. While there is no true perfect biomarker that predicts the
morbidity and mortality of SCA, %HbF was chosen as the primary endpoint as it is the most well-
established protective factor that is able to prevent polymerization of HbS and the subsequent
complications of SCA. While traditional therapy often achieves modest levels of HbF, we aim to maximize
the HbF response beyond the 30% level that has been postulated to be necessary to truly prevent HbS
polymerization and RBC sickling. Although safety is not a primary study endpoint, we will carefully collect
and analyze the frequency and severity …

Place your order
(550 words)

Approximate price: $22

Calculate the price of your order

550 words
We'll send you the first draft for approval by September 11, 2018 at 10:52 AM
Total price:
$26
The price is based on these factors:
Academic level
Number of pages
Urgency
Basic features
  • Free title page and bibliography
  • Unlimited revisions
  • Plagiarism-free guarantee
  • Money-back guarantee
  • 24/7 support
On-demand options
  • Writer’s samples
  • Part-by-part delivery
  • Overnight delivery
  • Copies of used sources
  • Expert Proofreading
Paper format
  • 275 words per page
  • 12 pt Arial/Times New Roman
  • Double line spacing
  • Any citation style (APA, MLA, Chicago/Turabian, Harvard)

Our guarantees

Delivering a high-quality product at a reasonable price is not enough anymore.
That’s why we have developed 5 beneficial guarantees that will make your experience with our service enjoyable, easy, and safe.

Money-back guarantee

You have to be 100% sure of the quality of your product to give a money-back guarantee. This describes us perfectly. Make sure that this guarantee is totally transparent.

Read more

Zero-plagiarism guarantee

Each paper is composed from scratch, according to your instructions. It is then checked by our plagiarism-detection software. There is no gap where plagiarism could squeeze in.

Read more

Free-revision policy

Thanks to our free revisions, there is no way for you to be unsatisfied. We will work on your paper until you are completely happy with the result.

Read more

Privacy policy

Your email is safe, as we store it according to international data protection rules. Your bank details are secure, as we use only reliable payment systems.

Read more

Fair-cooperation guarantee

By sending us your money, you buy the service we provide. Check out our terms and conditions if you prefer business talks to be laid out in official language.

Read more

Order your essay today and save 30% with the discount code HAPPY