GenotypeNCT01441141
Genetics and Pain Severity in Sickle Cell Disease
An observational study of Genotype and Pain, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
Background: Pain is the most common symptom of sickle cell disease. Episodes of severe sickle cell pain are known as "crises." High rates of pain crises are associated with a higher risk of early death. Some people with sickle cell disease have many severe pain crises while others experience fewer crises. Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- Genotype, Pain, Genetic Variation
- How many people
- 67 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Jun 2012to 9 Dec 2020
- 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 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: primary clinical
Who may be able to join
- Diagnosis of sickle cell disease (documentation of SS, SC, S beta + thalassemia, S beta + thalassemia by electrophoresis is required).
- If taking chronic analgesics (NSAID, acetaminophen) or opioids, study subjects should be on a stable dose for 4 weeks prior to recruitment.
- Hemoglobin AA genotype by HPLC or hemoglobin electrophoresis.
- General good health defined as the absence of untreated major medical conditions (e.g. uncontrolled systemic hypertension, etc.).
Who cannot join
- History of severe vaso-occlusive pain crisis resulting in either evaluation in an emergency department or admission to a hospital during the two weeks prior to study enrollment.
- Acute pain at the time of enrollment defined as spontaneous recent onset pain with a self rated score of 6 or higher on a scale of 0-10. (This is acute pain not the pain that subjects function at on a daily basis.)
- Acute pain or injury at enrollment or a recent history of chronic pain (daily pain reported for at least 6 months) in the past 3 years.
- Major medical/psychiatric illness known to cause pain.
- Sickle cell trait.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Exploratory Studies of Psychophysical Pain Phenotyping and Genetic Variability in Sickle Cell Disease
Background:
- Pain is the most common symptom of sickle cell disease. Episodes of severe sickle cell pain are known as "crises." High rates of pain crises are associated with a higher risk of early death. Some people with sickle cell disease have many severe pain crises while others experience fewer crises. This difference in pain crisis may be caused by sensitivity to pain. People with high sensitivity to pain may have more pain crises. Many factors, including a person's genetic makeup, determine sensitivity to pain. Comparing genetic information from people with sickle cell disease and healthy volunteers may provide more information on pain and sickle cell disease.
Read more
Objectives:
- To study genetics and pain sensitivity in sickle cell disease.
Eligibility:
- African or African American individuals at least 18 years of age with sickle cell disease.
- Healthy African or African American volunteers at least 18 years of age.
Design:
- Participants will be screened with a medical history and physical exam. They will also provide blood and urine samples.
- Participants will have the following tests:
- Quantitative sensory testing to measure sensitivity to pressure, heat, cold, and mechanical pain.
- EndoPat test to measure blood vessel function and reaction.
- Questionnaires about mood, evidence of depression, pain, quality of sleep, and sleep disturbances.
- Measures of daily pain, whether or not related to sickle cell disease.
- After the first visit, those in the study will have monthly study visits for 6 months. The above tests will be repeated at these visits.
Read the detailed description
Sickle cell disease (SCD) is the most common genetic disease in the United States inherited as an autosomal recessive disorder, where approximately 70,000 individuals have sickle cell disease. Acute painful vaso-occlusive crisis (VOCs) is one of the common complications of SCD that influences overall survival (Platt, Thorington et al. 1991). Pain, is also the most common cause of SCD morbidity, which has a negative impact on quality of life of these individuals and their families. There is significant inter-individual variation in the frequency and course of severe VOCs that result in hospital based treatment, the reasons for which have not been clearly elucidated. Vaso-occlusion of irreversibly sickle red cells within the microcirculation is believed to be the proximate cause of painful VOCs, however it is likely that other non-SCD related factors affecting pain perception and sensitivity to pain will also contribute to individuals susceptibility to pain and therefore contribute to the observed inter-individual variability in the course of VOC. Early identification of individuals who are at high risk for developing severe pain related morbidity and chronic pain syndromes is crucial since early multimodal interventions might have the potential to minimize both the morbidity and mortality associated with VOCs.
<TAB>
Patients with SCD are hypothesized to have lower nitric oxide (NO) bioavailability due to NO scavenging by cell free hemoglobin released into plasma during red cell hemolysis. NO deficiency has been identified as a key factor in development vascular dysfunction in SCD. NO has also recently been identified as a key mediator in processing nociceptive signals and modulation of pain in non-SCD models. Thus, low NO is associated with lower pain perception (Meller, Dykstra et al. 1992; Tegeder, Costigan et al. 2006). GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for synthesis of an essential cofactor for both NO production and metabolism of aromatic amino acids, namely tetrahydrobiopterin (BH4). Therefore it is hypothesized that genetic variants in the GCH1 gene will affect BH4 levels and which will have a secondary impact on vascular dysfunction and sensitivity to pain in SCD.
The primary goal of this protocol is to establish patterns of sensitivity to experimental pain among subjects with SCD compared to healthy African American controls. In addition, an exploratory analysis will determine if increased sensitivity to experimental pain correlates with the frequency and intensity of clinical pain in those with SCD. Once an expected pattern of experimental pain phenotypes are established for a cohort with SCD, we will then further explore the role of GCH1 genetic variants in experimental pain perception and vascular function. If successful, a longer term secondary objective is to establish a sufficiently large patient cohort with experimental pain phenotypes for future exploratory genetic studies to investigate the role of other loci that might influence sensitivity to experimental pain and vascular function in SCD.
- Conditions
- Genotype, Pain, Genetic Variation, Quantitative Sensory Testing (QST), GCH1
- Keywords
- GCH1, Pain Sensitivity, Quantitative Sensory Testing (QST), Genetic Variation, Sickle Cell Anemia
- Medical subject headings
- Pain, Anemia, Sickle Cell
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 |
|---|---|---|
| Arm 1 | Subjects with SCD | |
| Arm 2 | Subjects without SCD |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine if thresholds for pain perception are lower in SCD than in non-SCD controls.
lower pain threshold in SCD than in non-SCD controls
Measured: Ongoing
Secondary outcomes (2)
To determine if SCD subjects with higher GCH1 activity have 1) lower pain perception thresholds, 2) a higher prevalence of pain/VOC, 3) altered vascular reactivity and 4) more frequent pain co-morbidities) compared to subjects who lack this.
Measured: Ongoing
To determine if variants in the GCH1 gene alter thresholds for pain perception in sickle cell disease.
Measured: Ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Sep 2011 (estimated)
- Study start17 Jun 2012
- Primary completion31 May 2016
- Study completion9 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for GenotypeStudies 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
- Other
- Enrolment
- 67 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
- NCT01441141
- Sponsor's protocol ID
- 110252
- Other IDs
- 11-H-0252
- Status last verified
- Dec 2020
- First submitted
- 24 Sep 2011
- Last updated
- 10 Dec 2020
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, Orringer EP. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol. 2006 Jul;134(1):109-15. doi: 10.1111/j.1365-2141.2006.06110.x.
PubMed 16803576Bookman EB, Langehorne AA, Eckfeldt JH, Glass KC, Jarvik GP, Klag M, Koski G, Motulsky A, Wilfond B, Manolio TA, Fabsitz RR, Luepker RV; NHLBI Working Group. Reporting genetic results in research studies: summary and recommendations of an NHLBI working group. Am J Med Genet A. 2006 May 15;140(10):1033-40. doi: 10.1002/ajmg.a.31195.
PubMed 16575896Campbell CM, Kronfli T, Buenaver LF, Smith MT, Berna C, Haythornthwaite JA, Edwards RR. Situational versus dispositional measurement of catastrophizing: associations with pain responses in multiple samples. J Pain. 2010 May;11(5):443-453.e2. doi: 10.1016/j.jpain.2009.08.009.
PubMed 20439057Darbari DS, Vaughan KJ, Roskom K, Seamon C, Diaw L, Quinn M, Conrey A, Schechter AN, Haythornthwaite JA, Waclawiw MA, Wallen GR, Belfer I, Taylor JG 6th. Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia. Scand J Pain. 2017 Oct;17:279-286. doi: 10.1016/j.sjpain.2017.08.001. Epub 2017 Sep 30.
PubMed 28969994
Study at a glance
From the registry record, last updated by the sponsor on 10 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exploratory Studies of Psychophysical Pain Phenotyping and Genetic Variability in Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT01441141
- Acronym / sponsor ID
- 110252
- Conditions
- Genotype, Pain, Genetic Variation, Quantitative Sensory Testing (QST), GCH1
- Keywords
- GCH1, Pain Sensitivity, Quantitative Sensory Testing (QST), Genetic Variation, Sickle Cell Anemia
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 67 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 17 Jun 2012 (actual)
- Primary completion
- 31 May 2016 (actual)
- Study completion
- 9 Dec 2020 (actual)
- First posted
- 27 Sep 2011 (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.
Background:
- Pain is the most common symptom of sickle cell disease. Episodes of severe sickle cell pain are known as "crises." High rates of pain crises are associated with a higher risk of early death. Some people with sickle cell disease have many severe pain crises while others experience fewer crises. This difference in pain crisis may be caused by sensitivity to pain. People with high sensitivity to pain may have more pain crises. Many factors, including a person's genetic makeup, determine sensitivity to pain. Comparing genetic information from people with sickle cell disease and healthy volunteers may provide more information on pain and sickle cell disease.
Objectives:
- To study genetics and pain sensitivity in sickle cell disease.
Eligibility:
- African or African American individuals at least 18 years of age with sickle cell disease.
- Healthy African or African American volunteers at least 18 years of age.
Design:
- Participants will be screened with a medical history and physical exam. They will also provide blood and urine samples.
- Participants will have the following tests:
- Quantitative sensory testing to measure sensitivity to pressure, heat, cold, and mechanical pain.
- EndoPat test to measure blood vessel function and reaction.
- Questionnaires about mood, evidence of depression, pain, quality of sleep, and sleep disturbances.
- Measures of daily pain, whether or not related to sickle cell disease.
- After the first visit, those in the study will have monthly study visits for 6 months. The above tests will be repeated at these visits.
Detailed description
Sickle cell disease (SCD) is the most common genetic disease in the United States inherited as an autosomal recessive disorder, where approximately 70,000 individuals have sickle cell disease. Acute painful vaso-occlusive crisis (VOCs) is one of the common complications of SCD that influences overall survival (Platt, Thorington et al. 1991). Pain, is also the most common cause of SCD morbidity, which has a negative impact on quality of life of these individuals and their families. There is significant inter-individual variation in the frequency and course of severe VOCs that result in hospital based treatment, the reasons for which have not been clearly elucidated. Vaso-occlusion of irreversibly sickle red cells within the microcirculation is believed to be the proximate cause of painful VOCs, however it is likely that other non-SCD related factors affecting pain perception and sensitivity to pain will also contribute to individuals susceptibility to pain and therefore contribute to the observed inter-individual variability in the course of VOC. Early identification of individuals who are at high risk for developing severe pain related morbidity and chronic pain syndromes is crucial since early multimodal interventions might have the potential to minimize both the morbidity and mortality associated with VOCs.
<TAB>
Patients with SCD are hypothesized to have lower nitric oxide (NO) bioavailability due to NO scavenging by cell free hemoglobin released into plasma during red cell hemolysis. NO deficiency has been identified as a key factor in development vascular dysfunction in SCD. NO has also recently been identified as a key mediator in processing nociceptive signals and modulation of pain in non-SCD models. Thus, low NO is associated with lower pain perception (Meller, Dykstra et al. 1992; Tegeder, Costigan et al. 2006). GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for synthesis of an essential cofactor for both NO production and metabolism of aromatic amino acids, namely tetrahydrobiopterin (BH4). Therefore it is hypothesized that genetic variants in the GCH1 gene will affect BH4 levels and which will have a secondary impact on vascular dysfunction and sensitivity to pain in SCD.
The primary goal of this protocol is to establish patterns of sensitivity to experimental pain among subjects with SCD compared to healthy African American controls. In addition, an exploratory analysis will determine if increased sensitivity to experimental pain correlates with the frequency and intensity of clinical pain in those with SCD. Once an expected pattern of experimental pain phenotypes are established for a cohort with SCD, we will then further explore the role of GCH1 genetic variants in experimental pain perception and vascular function. If successful, a longer term secondary objective is to establish a sufficiently large patient cohort with experimental pain phenotypes for future exploratory genetic studies to investigate the role of other loci that might influence sensitivity to experimental pain and vascular function in SCD.
Study design
- Observational model
- Case-control
- Time perspective
- Other
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | – | –Subjects with SCD |
| Arm 2 | – | –Subjects without SCD |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- primary clinical
Key inclusion criteria (4 listed)
- Diagnosis of sickle cell disease (documentation of SS, SC, S beta + thalassemia, S beta + thalassemia by electrophoresis is required).
- If taking chronic analgesics (NSAID, acetaminophen) or opioids, study subjects should be on a stable dose for 4 weeks prior to recruitment.
- Hemoglobin AA genotype by HPLC or hemoglobin electrophoresis.
- General good health defined as the absence of untreated major medical conditions (e.g. uncontrolled systemic hypertension, etc.).
Key exclusion criteria (5 listed)
- History of severe vaso-occlusive pain crisis resulting in either evaluation in an emergency department or admission to a hospital during the two weeks prior to study enrollment.
- Acute pain at the time of enrollment defined as spontaneous recent onset pain with a self rated score of 6 or higher on a scale of 0-10. (This is acute pain not the pain that subjects function at on a daily basis.)
- Acute pain or injury at enrollment or a recent history of chronic pain (daily pain reported for at least 6 months) in the past 3 years.
- Major medical/psychiatric illness known to cause pain.
- Sickle cell trait.
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
To determine if thresholds for pain perception are lower in SCD than in non-SCD controls.
Time frame: Ongoing
lower pain threshold in SCD than in non-SCD controls
2 secondary outcomes
To determine if SCD subjects with higher GCH1 activity have 1) lower pain perception thresholds, 2) a higher prevalence of pain/VOC, 3) altered vascular reactivity and 4) more frequent pain co-morbidities) compared to subjects who lack this.
Time frame: Ongoing
To determine if variants in the GCH1 gene alter thresholds for pain perception in sickle cell disease.
Time frame: Ongoing
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 10 Dec 2020.
- Background: PubMed 16803576Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, Orringer EP. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol. 2006 Jul;134(1):109-15. doi: 10.1111/j.1365-2141.2006.06110.x.
- Background: PubMed 16575896Bookman EB, Langehorne AA, Eckfeldt JH, Glass KC, Jarvik GP, Klag M, Koski G, Motulsky A, Wilfond B, Manolio TA, Fabsitz RR, Luepker RV; NHLBI Working Group. Reporting genetic results in research studies: summary and recommendations of an NHLBI working group. Am J Med Genet A. 2006 May 15;140(10):1033-40. doi: 10.1002/ajmg.a.31195.
- Background: PubMed 20439057Campbell CM, Kronfli T, Buenaver LF, Smith MT, Berna C, Haythornthwaite JA, Edwards RR. Situational versus dispositional measurement of catastrophizing: associations with pain responses in multiple samples. J Pain. 2010 May;11(5):443-453.e2. doi: 10.1016/j.jpain.2009.08.009.
- Derived from this study: PubMed 28969994Darbari DS, Vaughan KJ, Roskom K, Seamon C, Diaw L, Quinn M, Conrey A, Schechter AN, Haythornthwaite JA, Waclawiw MA, Wallen GR, Belfer I, Taylor JG 6th. Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia. Scand J Pain. 2017 Oct;17:279-286. doi: 10.1016/j.sjpain.2017.08.001. Epub 2017 Sep 30.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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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 Genotype and Pain, 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 4 inclusion and 5 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 10 Dec 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.
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?
To determine if thresholds for pain perception are lower in SCD than in non-SCD controls. (time frame: Ongoing). 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 NCT01441141, which also lists 4 linked publications.
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 10 Dec 2020.