Sickle Cell DiseaseNCT03049475
Pathophysiology of Acute Pain in Patients With Sickle Cell Disease
An observational study of Sickle Cell Disease, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
Background: Sickle Cell Disease (SCD) is a blood disorder that occurs mainly in people of African descent. Researchers want to learn more about the painful attacks and complications associated with SCD. They want to look for a relationship between SCD and specific changes in the blood. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Sickle Cell Disease
- How many people
- 99 participants
- Where
- 1 siteUnited States
- Study dates
- 13 Mar 2017to 9 Dec 2019
- Phase
- Observational
- 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 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: 60 subjects with sickle cell disease 40 healthy individuals to serve as controls
Who may be able to join
- Between 18 and 80 years of age
- African, of African descent
- Ability to provide informed written consent
Who cannot join
- Pregnancy
- Diagnosis of with any of the following chronic disease or conditions:
- Sickle cell disease or sickle cell trait
- Uncontrolled high blood pressure (systolic blood pressure must not be greater than 160 mmHg or diastolic pressure greater than 90 mmHg
- Uncontrolled diabetes (must not have both a documented history of diabetes and random blood glucose of greater than 200 mg/dL)
- History of coronary artery disease
- History of congestive heart failure
- Chronic kidney disease (serum creatinine must not be greater than 2mg/dL)
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Background:
Sickle Cell Disease (SCD) is a blood disorder that occurs mainly in people of African descent. Researchers want to learn more about the painful attacks and complications associated with SCD. They want to look for a relationship between SCD and specific changes in the blood. They want to study the role of genetics, inflammation, and blood clotting factors in SCD. They will do this with blood samples collected during an acute painful attack and in between attacks.
Read more
Objective:
To learn more about the painful attacks and complications associated with SCD.
Eligibility:
People ages 18-80 with SCD or who are healthy Africans or African Americans without SCD
Design:
- Participants will be screened with medical history and physical exam.
- Healthy participants will have one visit.
- Participants with SCD will have their first visit when they are not having a pain attack. They will have their next visit during a pain attack. About 3-4 months after this attack, they will have a final visit.
- Visits will include a physical exam, and blood and urine tests.
- Participants may have their blood samples used for genetic testing for research.
Read the detailed description
Episodic pain is the most common acute morbidity and the leading cause of hospitalization in patients with sickle cell disease. It is caused by microvaso-occlusion induced by sickled red blood cells, an outcome of the polymerization of deoxygenated hemoglobin S (HbS). Factors that contribute to the acute sickle pain include the release of cell-free DNA (cfDNA) and heme that initiate a downstream of events involving inflammation and thrombosis, and ischemia-reperfusion injury.
Cell-free DNA has been shown to be present in plasma of healthy subjects, but elevated in diseases and conditions that are characterized by increased cell death through necrosis or apoptosis. Indeed, we have previously shown that cfDNA in patients with sickle cell disease (SCD) increased dramatically during acute painful episodes. During acute sickle pain, marked elevation of plasma hemoglobin has also been observed due to the acute increase in sickled red blood cells and hemolysis. Both cfDNA and heme (break down product of hemoglobin), act as damage-associated molecular pattern (DAMP) molecules, initiating endothelial inflammation, stimulation of neutrophil extracellular trap (NET) formation, leukocyte recruitment, and microvascular thrombosis.
Although there have been several studies of cytokines and chemokines in steady state and acute sickle cell disease, there has been no comprehensive study of how the inflammatory markers correlate with quantitative levels and profile of cfDNA. In this study, we would like to apply next generation sequencing (NGS) to analyze cfDNA from the plasma of patients with SCD in steadystate, and during painful crises to derive insights on the origin of tissue damage. In parallel with the free plasma DNA, we propose to measure markers of hemolysis and inflammation (cytokines, chemokines), and to investigate if interactions between these circulating molecules and blood cells (e.g. neutrophils) have the potential to modulate the progress and severity of the disease. In addition, we would also like to explore if there is a distinctive cell-free DNA and inflammatory signature in SCD in steady-state and during acute vaso-occlusive crises.
Overall, this study provides an opportunity to evaluate new biomarkers of sickle cell pain crisis and to predict disease severity and prognosis. These measures may allow us to better understand the role of vaso-occlusion, hemolysis, and inflammation-related events and responses and serve as clinical endpoints in future studies of disease pathogenesis and/or therapeutic intervention for sickle cell disease.
- Conditions
- Sickle Cell Disease
- Keywords
- Pain, Cell Free DNA, Inflammatory Markers, Microparticles, NETosis, Natural History
- Medical subject headings
- Anemia, Sickle Cell, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Control | Healthy, between age 18-80, African/African decent | |
| Subjects in steady State | Steady state is defined as the period from at any time 8 weeks prior to or after a crisis and samples obtained during this time would be considered steady state samples . |
What is being measured
The primary outcome is the main question the study is designed to answer.
1. To measure and compare defined sets of markers of obstruction of blood vessels (vaso-occlusion), red cell breakdown (hemolysis), and inflammation during acute painful crisis vs steady state in patients with sickle cell disease.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Feb 2017
- Study start13 Mar 2017
- Primary completion9 Dec 2019
- Study completion9 Dec 2019
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 National Heart, Lung, and Blood Institute (NHLBI)The 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
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 99 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Swee Lay Thein, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03049475
- Sponsor's protocol ID
- 170056
- Other IDs
- 17-H-0056
- Status last verified
- 24 Jun 2026
- First submitted
- 9 Feb 2017
- Last updated
- 29 Oct 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: The team is working on a decision.
Publications
Tumburu L, Ghosh-Choudhary S, Seifuddin FT, Barbu EA, Yang S, Ahmad MM, Wilkins LHW, Tunc I, Sivakumar I, Nichols JS, Dagur PK, Yang S, Almeida LEF, Quezado ZMN, Combs CA, Lindberg E, Bleck CKE, Zhu J, Shet AS, Chung JH, Pirooznia M, Thein SL. Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease. Blood. 2021 Jun 3;137(22):3116-3126. doi: 10.1182/blood.2020009063.
PubMed 33661274
Study at a glance
From the registry record, last updated by the sponsor on 29 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pathophysiology of Acute Pain in Patients With Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT03049475
- Acronym / sponsor ID
- 170056
- Conditions
- Sickle Cell Disease
- Keywords
- Pain, Cell Free DNA, Inflammatory Markers, Microparticles, NETosis, Natural History
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 99 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 13 Mar 2017 (actual)
- Primary completion
- 9 Dec 2019 (actual)
- Study completion
- 9 Dec 2019 (actual)
- First posted
- 10 Feb 2017 (actual)
- 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.
Background:
Sickle Cell Disease (SCD) is a blood disorder that occurs mainly in people of African descent. Researchers want to learn more about the painful attacks and complications associated with SCD. They want to look for a relationship between SCD and specific changes in the blood. They want to study the role of genetics, inflammation, and blood clotting factors in SCD. They will do this with blood samples collected during an acute painful attack and in between attacks.
Objective:
To learn more about the painful attacks and complications associated with SCD.
Eligibility:
People ages 18-80 with SCD or who are healthy Africans or African Americans without SCD
Design:
- Participants will be screened with medical history and physical exam.
- Healthy participants will have one visit.
- Participants with SCD will have their first visit when they are not having a pain attack. They will have their next visit during a pain attack. About 3-4 months after this attack, they will have a final visit.
- Visits will include a physical exam, and blood and urine tests.
- Participants may have their blood samples used for genetic testing for research.
Detailed description
Episodic pain is the most common acute morbidity and the leading cause of hospitalization in patients with sickle cell disease. It is caused by microvaso-occlusion induced by sickled red blood cells, an outcome of the polymerization of deoxygenated hemoglobin S (HbS). Factors that contribute to the acute sickle pain include the release of cell-free DNA (cfDNA) and heme that initiate a downstream of events involving inflammation and thrombosis, and ischemia-reperfusion injury.
Cell-free DNA has been shown to be present in plasma of healthy subjects, but elevated in diseases and conditions that are characterized by increased cell death through necrosis or apoptosis. Indeed, we have previously shown that cfDNA in patients with sickle cell disease (SCD) increased dramatically during acute painful episodes. During acute sickle pain, marked elevation of plasma hemoglobin has also been observed due to the acute increase in sickled red blood cells and hemolysis. Both cfDNA and heme (break down product of hemoglobin), act as damage-associated molecular pattern (DAMP) molecules, initiating endothelial inflammation, stimulation of neutrophil extracellular trap (NET) formation, leukocyte recruitment, and microvascular thrombosis.
Although there have been several studies of cytokines and chemokines in steady state and acute sickle cell disease, there has been no comprehensive study of how the inflammatory markers correlate with quantitative levels and profile of cfDNA. In this study, we would like to apply next generation sequencing (NGS) to analyze cfDNA from the plasma of patients with SCD in steadystate, and during painful crises to derive insights on the origin of tissue damage. In parallel with the free plasma DNA, we propose to measure markers of hemolysis and inflammation (cytokines, chemokines), and to investigate if interactions between these circulating molecules and blood cells (e.g. neutrophils) have the potential to modulate the progress and severity of the disease. In addition, we would also like to explore if there is a distinctive cell-free DNA and inflammatory signature in SCD in steady-state and during acute vaso-occlusive crises.
Overall, this study provides an opportunity to evaluate new biomarkers of sickle cell pain crisis and to predict disease severity and prognosis. These measures may allow us to better understand the role of vaso-occlusion, hemolysis, and inflammation-related events and responses and serve as clinical endpoints in future studies of disease pathogenesis and/or therapeutic intervention for sickle cell disease.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control | – | –Healthy, between age 18-80, African/African decent |
| Subjects in steady State | – | –Steady state is defined as the period from at any time 8 weeks prior to or after a crisis and samples obtained during this time would be considered steady state samples . |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- 60 subjects with sickle cell disease 40 healthy individuals to serve as controls
Key inclusion criteria (3 listed)
- Between 18 and 80 years of age
- African, of African descent
- Ability to provide informed written consent
Key exclusion criteria (8 listed)
- Pregnancy
- Diagnosis of with any of the following chronic disease or conditions:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
1. To measure and compare defined sets of markers of obstruction of blood vessels (vaso-occlusion), red cell breakdown (hemolysis), and inflammation during acute painful crisis vs steady state in patients with sickle cell disease.
Time frame: 1 year
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 29 Oct 2026.
- Derived from this study: PubMed 33661274Tumburu L, Ghosh-Choudhary S, Seifuddin FT, Barbu EA, Yang S, Ahmad MM, Wilkins LHW, Tunc I, Sivakumar I, Nichols JS, Dagur PK, Yang S, Almeida LEF, Quezado ZMN, Combs CA, Lindberg E, Bleck CKE, Zhu J, Shet AS, Chung JH, Pirooznia M, Thein SL. Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease. Blood. 2021 Jun 3;137(22):3116-3126. doi: 10.1182/blood.2020009063.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided. The team is working on a decision.
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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.
Swee Lay Thein, M.D. principal investigator
National Heart, Lung, and Blood Institute (NHLBI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Sickle Cell Disease, run by National Heart, Lung, and Blood Institute (NHLBI) 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 3 inclusion and 8 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 29 Oct 2026. 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.
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?
1. To measure and compare defined sets of markers of obstruction of blood vessels (vaso-occlusion), red cell breakdown (hemolysis), and inflammation during acute painful crisis vs steady state in patients with sickle cell disease. (time frame: 1 year). 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 NCT03049475, 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 29 Oct 2026.