Sickle Cell DiseaseEarly Phase 1NDEPTHNCT02042222
Novel Dose Escalation to Predict Treatment With Hydroxyurea
A Early Phase 1 study testing Hydroxyurea in people with Sickle Cell Disease, run by Baylor College of Medicine at 1 site in United States.
Trial summary
Sickle cell disease is a disorder in which red blood cells (RBCs) are abnormally shaped. This can result in painful episodes, serious infections, chronic anemia (a decrease in the number of red blood cells), and damage to body organs. Read more about this study
- Who is it for?
- Ages 1 year to 16 years
- Conditions the study is for
- Sickle Cell Disease
- What is being tested?
- Hydroxyurea
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2013to 31 Jul 2020
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 16 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- A severe form of sickle cell disease (HbSS or HbS beta-zero thalassemia)
- Age range of 1.0-15.99 years, inclusive, at the time of enrollment
- A decision by the subject's family and primary clinician to initiate hydroxyurea therapy, made independently of recruitment for the study (not applicable for the biological arm patients)
- Informed consent and assent (as applicable) obtained from parent/guardian and child.
- Ability to comply with all study related treatments, evaluations, and follow-up/study exit
Who cannot join
- Documented clinical stroke or transient ischemic attack (TIA).
- Known severe vasculopathy or moya-moya disease on brain imaging studies
- Asparagine aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times upper limit of normal or serum creatinine greater than 0.8 mg/dl
- Current participation in other interventional trials. Subjects must have been off any alternative therapy for at least three months prior to enrollment in this study
- Erythrocyte transfusion within the prior 2 months
- Any condition or chronic illness that in the opinion of the primary clinician makes participation in the trial ill advised
Show all 9Show fewer
- Inability or unwillingness to complete required studies
- Pregnancy or unwillingness to use a medically acceptable form of contraception if sexually active (male OR female)
- Patients excluded from participation due to laboratory abnormalities, participation in other interventional trials, or recent transfusions may be re-screened at a later date
Trial locations and contacts
1 site in 1 country.
About this study
Sickle cell disease is a disorder in which red blood cells (RBCs) are abnormally shaped. This can result in painful episodes, serious infections, chronic anemia (a decrease in the number of red blood cells), and damage to body organs. Hydroxyurea therapy offers significant benefits for infants, children, and adolescents with sickle cell anemia. These include a reduction in the frequency of pain crises and acute chest syndrome (inflammation of the lungs) and an increase in hemoglobin (the oxygen-carrying protein) in the blood. Patients on hydroxyurea who receive a maximum tolerated dose (MTD) that is specific for them have greater clinical benefit than those who receive a standard lower dose. There is, however, no way currently to predict the MTD for individual patients. As such, MTD for each patient is currently determined by gradual increases in the dose over several months. This process is time-consuming, requires monthly clinic visits, and delays the benefits of hydroxyurea therapy.
Our research group has come up with an equation that could be used to predict each patient's MTD using baseline clinical and laboratory measures before starting hydroxyurea treatment. The purpose of this research study is to compare the use of our equation for predicting MTD to the current standard practice of gradually increasing the hydroxyurea dose until MTD is reached. We want to see if the use of our predictive equation will allow us to achieve MTD faster and with no more side effects than with the standard practice.
Read the detailed description
To be eligible to participate in this study, patients must have decided that they want to begin hydroxyurea therapy. Patients choosing to participate in this study will be assigned randomly (like flipping a coin) to one of two hydroxyurea treatment groups. Both groups of patients will receive hydroxyurea treatment, but the determination of the starting hydroxyurea dose will be different between the two groups:
- Group 1: The standard (dose increase) group: Patients assigned to this group will be treated following the method that is currently standard for all patients starting hydroxyurea at our institution. All patients will be started at a dose of 20 milligrams per kilogram of body weight. Dose changes will be made every eight weeks until the patient is judged to be at his or her MTD.
- Group 2: The alternative (dose-prediction) group: Patients assigned to this group will have their predicted MTD determined using our dose-prediction equation and will be started directly at this dose.
Patients in both groups will be assessed monthly to see if they are having any side effects to hydroxyurea. We will also check to see if the MTD has been reached. Once it is decided that the patient has reached their maximum dose, they will continue to be monitored for two additional clinic visits (approximately eight additional weeks) to complete collection of end-of-study biological blood and urine samples and to ensure that there is no late harmful effects from hydroxyurea. The maximum time the patient will be on the study is 12 months after starting hydroxyurea therapy.
Patients will also be asked to participate in optional associated studies.
Biologic studies: The purpose of these studies is to determine the effect of hydroxyurea therapy on blood and urine markers that may be increased or decreased because of sickle cell disease. Patients participating in these studies will have one blood sample of 2 teaspoons (10 milliliters) and a urine sample collected before starting hydroxyurea therapy. Another blood and urine sample will be collected when they complete the study. These samples will be used to analyze markers associated with the following disease processes in sickle cell disease:
- inflammation, blood vessel damage and oxidative stress.
- blood viscosity.
- early kidney disease.
- early brain disease.
- altered function of white blood cells, red blood cells, and platelets.
- Conditions
- Sickle Cell Disease
- Being tested
- Hydroxyurea
- Keywords
- Sickle cell, Hydroxyurea, Dose prediction, Maximum tolerated dose
- Medical subject headings
- Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HydroxyureaDrug
Also called Siklos
| Study group | Role | What they receive |
|---|---|---|
| Standard Arm | Active comparator | Half of the subjects initiating hydroxyurea will be randomly assigned to the standard treatment arm, consisting of escalation to the maximum tolerated dose (MTD) of hydroxyurea utilizing a previously published algorithm. Hydroxyurea dosing will commence at 20+/-2.5 mg/kg/day, given as a single daily oral dose. All patients will be offered the choice of a liquid formulation of hydroxyurea or hydroxyurea tablets, with the exact dose rounded up or down to the closest practical dose based on the chosen formulation but not differing from the intended dose by more than 2.5 mg/kg. It should take approximately 6 to 12 months for subjects to reach the MTD on this arm. Receives: Drug: Hydroxyurea |
| Alternative Treatment Arm | Active comparator | Half of the subjects initiating hydroxyurea therapy will be assigned to the alternative treatment arm of the study. In this arm, the predicted hydroxyurea MTD will be calculated for each subject.
As in the dose-escalation arm, the exact dose will be rounded up or down to the closest practical dose based on the chosen formulation of hydroxyurea. Since the most common toxicity associated with hydroxyurea use is excessive myelosuppression, the maximum dose at which a subject in the dose-prediction arm will be started will be 30 mg/kg/day or 2000 mg/day. Patients with a higher predicted MTD will subsequently be escalated to this higher dose after four weeks on therapy if there is no evidence of toxicity. Receives: Drug: Hydroxyurea |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to patients reaching the maximum tolerated dose (MTD) of the medication
Compare the time required to achieve maximum tolerated dose (MTD) of the medication in a patient group treated using a MTD dose-prediction equation to that in a group on the standard dose escalation equation as measured in weeks for each study arm.
Measured: 6 months
Secondary outcomes (1)
Safety Analysis
Compare the frequency and severity of adverse events among patients in the dose-titration group to that among patients in the dose-prediction group. This as measured by the frequency and severity of excessive marrow suppression, renal or hepatic dysfunction, and skin and hair changes.
Collect clinical and laboratory data on subjects in both groups to retrospectively refine and modify current dose-prediction equations. This by the collection of basic biometric and laboratory data on patients, including baseline blood counts, markers of kidney function, and baseline and final hemoglobin F levels.
Determine the longitudinal effect of hydroxyurea therapy on laboratory measures of sickle cell pathophysiology such as blood viscosity and biomarkers of inflammation and vascular dysfunction. Measured by collection and comparison of baseline and final laboratory measures of the above parameters.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2014 (estimated)
- Study startOct 2013
- Primary completion31 Jul 2020
- Study completion31 Jul 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- More trials run by Baylor College of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baylor College of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Children's Hospital Medical Center, Cincinnati
- Responsible party
- Principal investigator, Titilope Fasipe, Baylor College of Medicine
- Investigators
- Alex George, MD, PhD, Principal investigator, Baylor College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02042222
- Sponsor's protocol ID
- H-32003 NDEPTH
- Acronym
- NDEPTH
- Status last verified
- Nov 2020
- First submitted
- 20 Jan 2014
- Last updated
- 18 Nov 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, Smeltzer MP, Kimble AC, Aygun B, Wu S, Howard T, Sparreboom A. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood. 2011 Nov 3;118(18):4985-91. doi: 10.1182/blood-2011-07-364190. Epub 2011 Aug 29.
PubMed 21876119
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Novel Dose Escalation to Predict Treatment With Hydroxyurea
- ClinicalTrials.gov ID
- NCT02042222
- Acronym / sponsor ID
- NDEPTH / H-32003 NDEPTH
- Conditions
- Sickle Cell Disease
- Keywords
- Sickle cell, Hydroxyurea, Dose prediction, Maximum tolerated dose
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- Baylor College of MedicineUniversity, hospital or other
- Collaborators
- Children's Hospital Medical Center, Cincinnati
- Study start
- Oct 2013 (actual)
- Primary completion
- 31 Jul 2020 (actual)
- Study completion
- 31 Jul 2020 (actual)
- First posted
- 22 Jan 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Sickle cell disease is a disorder in which red blood cells (RBCs) are abnormally shaped. This can result in painful episodes, serious infections, chronic anemia (a decrease in the number of red blood cells), and damage to body organs. Hydroxyurea therapy offers significant benefits for infants, children, and adolescents with sickle cell anemia. These include a reduction in the frequency of pain crises and acute chest syndrome (inflammation of the lungs) and an increase in hemoglobin (the oxygen-carrying protein) in the blood. Patients on hydroxyurea who receive a maximum tolerated dose (MTD) that is specific for them have greater clinical benefit than those who receive a standard lower dose. There is, however, no way currently to predict the MTD for individual patients. As such, MTD for each patient is currently determined by gradual increases in the dose over several months. This process is time-consuming, requires monthly clinic visits, and delays the benefits of hydroxyurea therapy.
Our research group has come up with an equation that could be used to predict each patient's MTD using baseline clinical and laboratory measures before starting hydroxyurea treatment. The purpose of this research study is to compare the use of our equation for predicting MTD to the current standard practice of gradually increasing the hydroxyurea dose until MTD is reached. We want to see if the use of our predictive equation will allow us to achieve MTD faster and with no more side effects than with the standard practice.
Detailed description
To be eligible to participate in this study, patients must have decided that they want to begin hydroxyurea therapy. Patients choosing to participate in this study will be assigned randomly (like flipping a coin) to one of two hydroxyurea treatment groups. Both groups of patients will receive hydroxyurea treatment, but the determination of the starting hydroxyurea dose will be different between the two groups:
- Group 1: The standard (dose increase) group: Patients assigned to this group will be treated following the method that is currently standard for all patients starting hydroxyurea at our institution. All patients will be started at a dose of 20 milligrams per kilogram of body weight. Dose changes will be made every eight weeks until the patient is judged to be at his or her MTD.
- Group 2: The alternative (dose-prediction) group: Patients assigned to this group will have their predicted MTD determined using our dose-prediction equation and will be started directly at this dose.
Patients in both groups will be assessed monthly to see if they are having any side effects to hydroxyurea. We will also check to see if the MTD has been reached. Once it is decided that the patient has reached their maximum dose, they will continue to be monitored for two additional clinic visits (approximately eight additional weeks) to complete collection of end-of-study biological blood and urine samples and to ensure that there is no late harmful effects from hydroxyurea. The maximum time the patient will be on the study is 12 months after starting hydroxyurea therapy.
Patients will also be asked to participate in optional associated studies.
Biologic studies: The purpose of these studies is to determine the effect of hydroxyurea therapy on blood and urine markers that may be increased or decreased because of sickle cell disease. Patients participating in these studies will have one blood sample of 2 teaspoons (10 milliliters) and a urine sample collected before starting hydroxyurea therapy. Another blood and urine sample will be collected when they complete the study. These samples will be used to analyze markers associated with the following disease processes in sickle cell disease:
- inflammation, blood vessel damage and oxidative stress.
- blood viscosity.
- early kidney disease.
- early brain disease.
- altered function of white blood cells, red blood cells, and platelets.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard Arm | Active comparator | Drug: HydroxyureaHalf of the subjects initiating hydroxyurea will be randomly assigned to the standard treatment arm, consisting of escalation to the maximum tolerated dose (MTD) of hydroxyurea utilizing a previously published algorithm. Hydroxyurea dosing will commence at 20+/-2.5 mg/kg/day, given as a single daily oral dose. All patients will be offered the choice of a liquid formulation of hydroxyurea or hydroxyurea tablets, with the exact dose rounded up or down to the closest practical dose based on the chosen formulation but not differing from the intended dose by more than 2.5 mg/kg. It should take approximately 6 to 12 months for subjects to reach the MTD on this arm. |
| Alternative Treatment Arm | Active comparator | Drug: HydroxyureaHalf of the subjects initiating hydroxyurea therapy will be assigned to the alternative treatment arm of the study. In this arm, the predicted hydroxyurea MTD will be calculated for each subject. As in the dose-escalation arm, the exact dose will be rounded up or down to the closest practical dose based on the chosen formulation of hydroxyurea. Since the most common toxicity associated with hydroxyurea use is excessive myelosuppression, the maximum dose at which a subject in the dose-prediction arm will be started will be 30 mg/kg/day or 2000 mg/day. Patients with a higher predicted MTD will subsequently be escalated to this higher dose after four weeks on therapy if there is no evidence of toxicity. |
Who may qualify
- Ages
- 1 year to 16 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- A severe form of sickle cell disease (HbSS or HbS beta-zero thalassemia)
- Age range of 1.0-15.99 years, inclusive, at the time of enrollment
- A decision by the subject's family and primary clinician to initiate hydroxyurea therapy, made independently of recruitment for the study (not applicable for the biological arm patients)
- Informed consent and assent (as applicable) obtained from parent/guardian and child.
- Ability to comply with all study related treatments, evaluations, and follow-up/study exit
Key exclusion criteria (9 listed)
- Documented clinical stroke or transient ischemic attack (TIA).
- Known severe vasculopathy or moya-moya disease on brain imaging studies
- Asparagine aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times upper limit of normal or serum creatinine greater than 0.8 mg/dl
- Current participation in other interventional trials. Subjects must have been off any alternative therapy for at least three months prior to enrollment in this study
- Erythrocyte transfusion within the prior 2 months
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HydroxyureaAlso: Siklos | Drug | Alternative Treatment Arm, Standard Arm |
Primary outcome
Time to patients reaching the maximum tolerated dose (MTD) of the medication
Time frame: 6 months
Compare the time required to achieve maximum tolerated dose (MTD) of the medication in a patient group treated using a MTD dose-prediction equation to that in a group on the standard dose escalation equation as measured in weeks for each study arm.
1 secondary outcome
Safety Analysis
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2020.
- Background: PubMed 21876119Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, Smeltzer MP, Kimble AC, Aygun B, Wu S, Howard T, Sparreboom A. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood. 2011 Nov 3;118(18):4985-91. doi: 10.1182/blood-2011-07-364190. Epub 2011 Aug 29.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alex George, MD, PhD principal investigator
Baylor College of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Hydroxyurea in people with Sickle Cell Disease, run by Baylor College of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to patients reaching the maximum tolerated dose (MTD) of the medication (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02042222, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2020.