Sickle Cell DiseasePhase 1ZileutonNCT01136941
Trial of Zileuton CR in Children and Adults With Sickle Cell Disease
A Phase 1 study testing Zileuton in people with Sickle Cell Disease, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.
Trial summary
The purpose of this research study is to test the safety of Zileuton and see what effects (good and bad) it has on you, other children and adults with Sickle Cell Disease (SCD). The investigators also want to see how Zileuton is handled by your body at different doses. Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Sickle Cell Disease
- What is being tested?
- Zileuton
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2010to Apr 2013
- Phase
- 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 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Confirmed diagnosis of SCD (HbSS,HbSC,HBS Beta thalassemia, or HBS 0 thalassemia)
- Absence of an acute sickle event or ACS in the last 4 wks
- Not on hydroxyurea
- Ability to swallow pills
- Ability to comply with pulmonary function testing
Who cannot join
- History of active hepatitis
- HIV positivity
- Pregnant or nursing
- Unable to comply with contraceptive measures
- On an investigational drug within 4 weeks
- On hydroxyurea, leukotriene antagonists (e.g., Singulair) or steroids, theophylline, coumadin, terfenadine or beta-2 blockers that affect the airway: carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, sotalol and timolol, or on propranolol for the last four weeks
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- On chronic transfusion therapy
- A serious, concurrent illness that would limit ability to complete or comply with the study requirements
- Males who drink alcoholic beverages >5-6 drinks/day or females who drink alcoholic beverages >3-4 drinks/day
Trial locations and contacts
1 site in 1 country.
United States1 site
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
About this study
Official title: Phase I Trial of Zileuton CR in Children and Adults With Sickle Cell Disease
The purpose of this research study is to test the safety of Zileuton and see what effects (good and bad) it has on you, other children and adults with Sickle Cell Disease (SCD). The investigators also want to see how Zileuton is handled by your body at different doses.
Zileuton is a drug that is approved by the Food and Drug Administration (FDA) for the treatment of asthma for people age 12 and older. The FDA has not approved Zileuton for the treatment of SCD, so it is being studied as an investigational drug for SCD through an application to the FDA. In asthma patients, Zileuton helps by reducing inflammation. This study will see if Zileuton helps to reduce inflammation associated with SCD.
Read the detailed description
Inflammation is now recognized as central to the pathophysiology of sickle cell disease (SCD), and is manifest as leukocytosis, elevated levels of inflammatory cytokines, and activation of monocytes, polymorphonuclear leukocytes (PMN) and endothelial cells. It is present at steady state and is strongly associated with acute events, acute chest and early mortality. Inflammation contributes to endothelial cell dysfunction, potentiates vaso-occlusion, and may also give rise to the airway hyper-reactivity (AHR) that often accompanies SCD. A spectrum of lung disease is seen in this patient population, from AHR and obstructive lung disease in children, to restrictive lung disease and pulmonary vascular remodeling in adults.
Evidence from our laboratory suggests that a specific angiogenic cytokine, Placenta Growth Factor that is produced by hyperplastic erythroid marrow cells and elevated in SCD, contributes to activation of monocytes and endothelial cells by inducing a key leukotriene (LT) synthetic enzyme, 5-Lipoxygenase (5LO). 5LO increases production of LT. LT are among the most potent inflammatory mediators known. LT-B4 is a very potent chemoattractant and activator of PMN and enhances endothelial cell activation, and cysteinyl LT produce airway smooth muscle constriction and inflammation in lung. Elevated LT-B4 and cysteinyl LT, and a high incidence of AHR are observed in patients with SCD. Zileuton (ZL) is a specific inhibitor of 5LO that decreases LT production, and is FDA-approved for treatment of asthma for individuals 12 years of age or older. In the context of SCD, ZL reduced adhesion of PMN and sickle RBC to rat pulmonary vasculature. In vitro data shows that ZL also increased fetal hemoglobin (HbF) production from erythroid cells in vitro, and could have additive/synergistic effects with hydroxyurea (HU). Thus, ZL may be beneficial in SCD by reducing inflammation, mitigating AHR, and increasing HbF.
We hypothesize that inhibition of 5LO activity with ZL will be safe, feasible; will significantly reduce leukotrienes and biomarkers of inflammation, will decrease AHR; and will induce HbF in patients with SCD.
We will test this hypothesis in a Phase I study of ZL in SCD. First, we will establish a safe dose of ZL and its pharmacokinetics in patients with SCD. The secondary objectives will be to determine its pharmacodynamic effects on biological endpoints and compliance to twice daily ZL administration.
- Conditions
- Sickle Cell Disease
- Being tested
- Zileuton
- 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.
ZileutonDrug
Zileuton is available as a 600 mg tablet. Dosing begins at 2.4gm/day and will be increased to 3.0gm/day. Tablets will be taken twice daily for the 6 week duration of the study.
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Experimental | Research participants will be administered Zileuton according to the dose escalation/de-escalation schema provided in the protocol. Receives: Drug: Zileuton |
What is being measured
The primary outcome is the main question the study is designed to answer.
Adverse Event Grading as a Measure of Safety and Tolerability
The drug will be considered safe and tolerable if there is no grade-4 toxicity and no irreversible grade-3 toxicity upon de-escalation or discontinuation. The dose for the Part 2 portion of the trial will be the dose at which there was no DLT in 5 out of 6 at highest dose level below the maximally administered dose.
Measured: Outcome measures will be assessed at all study visits. Visits occur at week 1, Week 2, Week 4 and Week 6. Follow-up assessments will take place at Weeks 8 and 10.
Characterization of the Distribution of Zileuton Pharmacokinetic Parameter Estimates and Drug Exposure
We do not anticipate a difference in PK from normal controls. PK analysis will be performed to verify steady state levels of ZL and LT are similar to normal controls.
Measured: Outcome measures will be assessed at study visits occurring at Visit 1, week 1, Week 2, Week 3 and Week 5.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jun 2010 (estimated)
- Study startSep 2010
- Primary completionApr 2013
- Study completionApr 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- More trials run by Children's Hospital Medical Center, CincinnatiThe 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
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Children's Hospital Medical Center, Cincinnati
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Punam Malik, MD, Principal investigator, Children's Hospital Medical Center, Cincinnati
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01136941
- Sponsor's protocol ID
- 2009-1622
- Acronym
- Zileuton
- Status last verified
- Jun 2014
- First submitted
- 13 May 2010
- Last updated
- 18 Jun 2014
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Trial of Zileuton CR in Children and Adults With Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT01136941
- Acronym / sponsor ID
- Zileuton / 2009-1622
- Conditions
- Sickle Cell Disease
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Children's Hospital Medical Center, CincinnatiUniversity, hospital or other
- Study start
- Sep 2010
- Primary completion
- Apr 2013 (actual)
- Study completion
- Apr 2013 (actual)
- First posted
- 4 Jun 2010 (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.
The purpose of this research study is to test the safety of Zileuton and see what effects (good and bad) it has on you, other children and adults with Sickle Cell Disease (SCD). The investigators also want to see how Zileuton is handled by your body at different doses.
Zileuton is a drug that is approved by the Food and Drug Administration (FDA) for the treatment of asthma for people age 12 and older. The FDA has not approved Zileuton for the treatment of SCD, so it is being studied as an investigational drug for SCD through an application to the FDA. In asthma patients, Zileuton helps by reducing inflammation. This study will see if Zileuton helps to reduce inflammation associated with SCD.
Detailed description
Inflammation is now recognized as central to the pathophysiology of sickle cell disease (SCD), and is manifest as leukocytosis, elevated levels of inflammatory cytokines, and activation of monocytes, polymorphonuclear leukocytes (PMN) and endothelial cells. It is present at steady state and is strongly associated with acute events, acute chest and early mortality. Inflammation contributes to endothelial cell dysfunction, potentiates vaso-occlusion, and may also give rise to the airway hyper-reactivity (AHR) that often accompanies SCD. A spectrum of lung disease is seen in this patient population, from AHR and obstructive lung disease in children, to restrictive lung disease and pulmonary vascular remodeling in adults.
Evidence from our laboratory suggests that a specific angiogenic cytokine, Placenta Growth Factor that is produced by hyperplastic erythroid marrow cells and elevated in SCD, contributes to activation of monocytes and endothelial cells by inducing a key leukotriene (LT) synthetic enzyme, 5-Lipoxygenase (5LO). 5LO increases production of LT. LT are among the most potent inflammatory mediators known. LT-B4 is a very potent chemoattractant and activator of PMN and enhances endothelial cell activation, and cysteinyl LT produce airway smooth muscle constriction and inflammation in lung. Elevated LT-B4 and cysteinyl LT, and a high incidence of AHR are observed in patients with SCD. Zileuton (ZL) is a specific inhibitor of 5LO that decreases LT production, and is FDA-approved for treatment of asthma for individuals 12 years of age or older. In the context of SCD, ZL reduced adhesion of PMN and sickle RBC to rat pulmonary vasculature. In vitro data shows that ZL also increased fetal hemoglobin (HbF) production from erythroid cells in vitro, and could have additive/synergistic effects with hydroxyurea (HU). Thus, ZL may be beneficial in SCD by reducing inflammation, mitigating AHR, and increasing HbF.
We hypothesize that inhibition of 5LO activity with ZL will be safe, feasible; will significantly reduce leukotrienes and biomarkers of inflammation, will decrease AHR; and will induce HbF in patients with SCD.
We will test this hypothesis in a Phase I study of ZL in SCD. First, we will establish a safe dose of ZL and its pharmacokinetics in patients with SCD. The secondary objectives will be to determine its pharmacodynamic effects on biological endpoints and compliance to twice daily ZL administration.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment | Experimental | Drug: ZileutonResearch participants will be administered Zileuton according to the dose escalation/de-escalation schema provided in the protocol. |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- Confirmed diagnosis of SCD (HbSS,HbSC,HBS Beta thalassemia, or HBS 0 thalassemia)
- Absence of an acute sickle event or ACS in the last 4 wks
- Not on hydroxyurea
- Ability to swallow pills
- Ability to comply with pulmonary function testing
Key exclusion criteria (9 listed)
- History of active hepatitis
- HIV positivity
- Pregnant or nursing
- Unable to comply with contraceptive measures
- On an investigational drug within 4 weeks
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 |
|---|---|---|
| ZileutonZileuton is available as a 600 mg tablet. Dosing begins at 2.4gm/day and will be increased to 3.0gm/day. Tablets will be taken twice daily for the 6 week duration of the study. | Drug | Treatment |
Primary outcome
Adverse Event Grading as a Measure of Safety and Tolerability
Time frame: Outcome measures will be assessed at all study visits. Visits occur at week 1, Week 2, Week 4 and Week 6. Follow-up assessments will take place at Weeks 8 and 10.
The drug will be considered safe and tolerable if there is no grade-4 toxicity and no irreversible grade-3 toxicity upon de-escalation or discontinuation. The dose for the Part 2 portion of the trial will be the dose at which there was no DLT in 5 out of 6 at highest dose level below the maximally administered dose.
Characterization of the Distribution of Zileuton Pharmacokinetic Parameter Estimates and Drug Exposure
Time frame: Outcome measures will be assessed at study visits occurring at Visit 1, week 1, Week 2, Week 3 and Week 5.
We do not anticipate a difference in PK from normal controls. PK analysis will be performed to verify steady state levels of ZL and LT are similar to normal controls.
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 Jun 2014.
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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.
Punam Malik, MD principal investigator
Children's Hospital Medical Center, Cincinnati
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Zileuton in people with Sickle Cell Disease, run by Children's Hospital Medical Center, Cincinnati 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 Jun 2014. 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?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Adverse Event Grading as a Measure of Safety and Tolerability (time frame: Outcome measures will be assessed at all study visits. Visits occur at week 1, Week 2, Week 4 and Week 6. Follow-up assessments will take place at Weeks 8 and 10.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 Jun 2014.