Assessment of Computerized Algorithm-Based Hydroxyurea Dosing on Fetal Hemoglobin Response, Acute Complications, and Organ Function in Subjects With Sickle Cell Disease
Assessment of Algorithm-Based Hydroxyurea Dosing on Fetal Hemoglobin Response, Acute Complications, and Organ Function in People With Sickle Cell Disease
Sponsors
Source
National Institutes of Health Clinical Center (CC)
Oversight Info
Is Fda Regulated Drug
Yes
Is Fda Regulated Device
No
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.
Overall Status
Completed
Start Date
2014-08-23
Completion Date
2018-05-24
Primary Completion Date
2018-05-24
Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
|
Fetal Hemoglobin Level |
Baseline |
|
Fetal Hemoglobin Level |
12 months |
Enrollment
10
Condition
Intervention
Intervention Type
Drug
Intervention Name
Description
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.
Arm Group Label
1
Eligibility
Criteria
- INCLUSION CRITERIA:
1. Age greater than or equal to 15 years
2. Homozygous sickle cell disease (HbSS)
3. Patients with recent transfusion must have HbA <15% prior to enrollment
4. ANC greater than or equal to 2,000/microL, platelets greater than or equal
to150,000/microL, Hb > 5.4g/dL, and ARC greater than or equal to100,000/microL
(unless the Hb is > 8g/dL) at baseline
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
EXCLUSION CRITERIA:
1. Pregnant or lactating women or patients planning to get pregnant during the study
period
2. Patients unwilling to use two forms of contraception throughout the period of HU
administration
3. Patients receiving chronic transfusion therapy
4. Patients receiving a HU dose of greater than or equal to 20 mg/kg/day
5. Patients with history of allergy or intolerance to HU judged by the investigator to be
prohibitive against restarting HU
6 Patients with end stage renal disease defined as GFR <10mL/min/1.73m(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.
8. Participation on any other chronic investigative treatment studies
9. Unable to understand the investigational nature of the study or give informed consent.
Gender
All
Minimum Age
15 Years
Maximum Age
99 Years
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
|
Courtney D Fitzhugh, M.D. |
Principal Investigator |
National Heart, Lung, and Blood Institute (NHLBI) |
Location
Facility |
|
National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland 20892 United States |
Location Countries
Country
United States
Verification Date
2019-04-25
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor
Keywords
Has Expanded Access
No
Condition Browse
Secondary Id
14-H-0172
Number Of Arms
1
Intervention Browse
Mesh Term
Hydroxyurea
Arm Group
Arm Group Label
1
Arm Group Type
Experimental
Description
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.
Firstreceived Results Date
N/A
Firstreceived Results Disposition Date
N/A
Study Design Info
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Study First Submitted
August 23, 2014
Study First Submitted Qc
August 23, 2014
Study First Posted
August 26, 2014
Last Update Submitted
July 15, 2019
Last Update Submitted Qc
July 15, 2019
Last Update Posted
August 6, 2019
Results First Submitted
July 15, 2019
Results First Submitted Qc
July 15, 2019
Results First Posted
August 6, 2019
Provided Document Section
Provided Document
Document Type
Study Protocol and Statistical Analysis Plan
Document Has Protocol
Yes
Document Has Icf
No
Document Has Sap
Yes
Document Date
August 23, 2016
Document Url
https://ClinicalTrials.gov/ProvidedDocs/32/NCT02225132/Prot_SAP_000.pdf
ClinicalTrials.gov processed this data on December 13, 2019
Conditions
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conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.