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Clinical Trials: Blood - Sickle Cell Disease
IRB No. 13-061-6 (Dr. Biree Andemariam, PI): CASIRE Sickle Cell Renal Disease Cohort International Study Protocol
Study description not available
IRB No. 14-107-6 (Dr. Biree Andemariam, PI): Identification of Patient-specific RBC-endothelial Cell Adhesion Profiles as Markers of Sickle Cell Disease Severity.
The research objective of this proposal is to determine in 25 adult/pediatric SCD patients (1) the relationship between pain severity phenotype and the strength of adhesion between single red blood cells (RBCs) and single endothelial cells (ECs) isolated from peripheral blood and (2) the ex vivo effect of pharmacologic inhibitors on RBC-EC adhesion, creating both a patient-specific adhesion profile and therapeutic signature. The results are expected to lead to novel individually-targeted approaches to inhibit the onset and limit the duration of painful vaso-occlusive episodes (VOEs). Our central hypothesis is that the strength of adhesion between RBCs and ECs at baseline is related to patient-specific pain severity phenotype, resulting in the need for patient-specific drug therapy. To test the hypothesis, we will pursue the following three specific aims: Investigate the relationship between pain severity phenotype and baseline RBC-EC adhesion profile in SCD subjects – We will measure the strength of adhesion between single RBCs-ECs from SCD subjects at baseline. Baseline/steady-state adhesion profiles will be compared on an inter-patient level to determine which adhesion profiles correlate most highly with pain severity phenotype. Assess the association of VOE severity with changes in RBC-EC adhesion from baseline to VOE onset. We will measure the change in strength of adhesion between single RBCs-ECs from baseline to VOE onset. Changes in adhesion will be compared on an inter-patient level to determine whether relative changes in adhesion profile at VOE onset correlate with VOE severity. Test the ex vivo effect of targeted pharmacotherapy on the RBC-EC adhesion profile of SCD subjects – We will measure (at baseline and at VOE onset) the ex vivo inhibitory effect of two known RBC-EC adhesion blockers (propranolol and abciximab) to identify patient-specific anti-adhesive therapeutic signatures.
IRB No. 14-136-6 (Dr. Biree Andemariam, PI): Hemoglobinopathies and Bone Health
This research study has two purposes. The first purpose is to determine whether having sickle cell trait is a risk factor for the development of bone thinning at an earlier age than expected. Nearly 10% of African Americans carry sickle cell trait and most of them are unaware of it. African Americans are less likely to develop thin bones than whites, but if they sustain a bone fracture, they are more likely to die from it. We believe having sickle cell trait may lead to bone thinning and predispose a subset of African Americans to dangerously thin bones. The second purpose is to try to understand why individuals with sickle cell disease have thinner bones than healthy individuals do. Doctors have already discovered that people with sickle cell disease have very thin bones, but they have not determined why. Our study will try to identify whether the bone thinning is from the body not making enough bone or from the body losing bone once it is made.
IRB No. 12-013S-3.2 (Dr. Biree Andemariam, PI): Biomechanical Properties of Blood Cells in Sickle Cell Disease
Study description not available
IRB No. 18-104-1 (Dr. Biree Andemariam, PI): A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study of IMR-687 in Adult Patients with Sickle Cell Anaemia (Homozygous HbSS or Sickle-ß0 Thalassemia)
A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study of IMR-687 in Adult Patients with Sickle Cell Anaemia (Homozygous HbSS or Sickle-Beta 0 Thalassemia) Background: With a neonatal incidence of 294,000 to 330,000 patients worldwide (Piel 2013), SCA is a rare inherited disorder of red blood cells (RBCs) that is both serious and life threatening. The most common manifestations of SCA include vaso-occlusive crisis, chronic and acute severe pain, acute chest syndrome, stroke, priapism, acute anaemia (particularly from aplastic crisis and splenic sequestration), increased susceptibility to infection, and progressive damage to major organs including the spleen, brain, kidney, heart, lung, skin, retina, vestibular cochlear systems, and bone. In developed countries where there is prenatal Screening and wide spread access to prophylactic and acute interventions, the median age of death remains in the 40s to 50s though many patients succumb to the disease much earlier. Rationale for the study: This is the first study in patients with SCA. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) and clinical outcomes of IMR-687 in adult patients with SCA. Given that approximately 25% of patients with SCA are currently prescribed HU, it is possible that IMR-687, should it be approved, will be administered as a single agent or co-administered with HU. Therefore, the effects of IMR-687 will be evaluated in patients with SCA who are not receiving HU (Population A) as well as those who are currently receiving a stable dose of HU according to standard of care (Population B). Study design: This is a randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and exploratory PD and clinical outcomes of the phosphodiesterase 9 (PDE9) inhibitor, IMR-687. Study population and sample size: 2 populations of patients with SCA: those who are not receiving HU (Population A) and those who are currently receiving a stable dose of HU according to standard of care (Population B). Up to approximately 36 patients will be enrolled in Population A and 18 patients will be enrolled in Population B. Major study interventions: IMR-687 will be supplied as 50, 100 or 200 mg white tablets and will be administered orally with food. Main outcome measures/analyses: Primary Objectives: To assess the safety and tolerability of IMR-687 in adult patients with sickle cell anaemia (SCA), defined as homozygous sickle haemoglobin (HbSS) or sickle-Beta-0 thalassemia, who are not receiving hydroxyurea (HU) and in adult SCA patients who are receiving a stable dose of HU Secondary Objectives: To characterise the pharmacokinetic (PK) profile of IMR-687 in adult patients with SCA who are/are not receiving a stable dose of HU To characterise the PK profile of HU in adult patients with SCA before and after receiving IMR-687 to determine if there is a clinically relevant PK interaction. Exploratory Objectives: To assess the pharmacodynamic (PD) effects of IMR-687 in adult patients with SCA who are/are not receiving stable HU To assess the potential efficacy of IMR-687 on SCA-related clinical outcome measures in adult patients with SCA who are/are not receiving stable HU
IRB No. 18-167-2: Assessment of Cardiac Abnormalities in Sickle Cell Patients Using Echocardiography
Assessment of Cardiac Abnormalities in Sickle Cell Patients Using Echocardiography
IRB No. 13-061C-6.2 (Dr. Biree Andemariam, PI): CASIRE Sickle Cell Renal Disease Cohort International Study Protocol
Study design: This study's design is cross-sectional. Our cross-sectional study approach will allow us to determine particular age cohorts (young children, adolescents and young adults) that might be at risk for developing early renal dysfunction. Further, it will also allow us to determine which estimates of GFR have the best correlation to the changes in renal function. Specifically, we will determine if estimates in GFR, increasing microalbuminuria, or blood pressure changes will be predictive of early renal dysfunction. Study procedures: The research staff, which includes study coordinators from UCHC and CCMC, co-investigators from CCMC, and a principal investigator from UCHC, will only enroll subjects with sickle cell disease who are at steady state and have not had an infection, pain crisis, emergency room visit or hospitalization within two weeks of the time that they are enrolled in the study. Subjects will be screened by the PI or co-investigators, with whom they have a treating relationship. Potential subjects will be told about the study by the PI or co-investigators during a routine clinical visit. Those potential subjects who verbalize interest in learning more about the study will then have an opportunity to discuss the study further with a member of the research staff. If the subject then verbalizes desire to participate, informed consent will be obtained. The questionnaire will then be administered in its entirety by a member of the research staff by verbally asking the subject to answer each question. If there is any uncertainty about the answer to a particular question, the medical chart will be reviewed for verification. We estimate it will take about 20-30 minutes for the subjects to fill out the questionnaire with a research staff member. The subject's involvement ends once the questionnaire is completed.
IRB No. 14-107CS-6.2 (Dr. Biree Andemariam, PI): Identification of Patient-specific RBC-endothelial Cell Adhesion Profiles as Markers of Sickle Cell Disease Severity.
The research objective of this proposal is to determine in 25 adult/pediatric SCD patients (1) the relationship between pain severity phenotype and the strength of adhesion between single red blood cells (RBCs) and single endothelial cells (ECs) isolated from peripheral blood and (2) the ex vivo effect of pharmacologic inhibitors on RBC-EC adhesion, creating both a patient-specific adhesion profile and therapeutic signature. The results are expected to lead to novel individually-targeted approaches to inhibit the onset and limit the duration of painful vaso-occlusive episodes (VOEs). Our central hypothesis is that the strength of adhesion between RBCs and ECs at baseline is related to patient-specific pain severity phenotype, resulting in the need for patient-specific drug therapy. To test the hypothesis, we will pursue the following three specific aims: Investigate the relationship between pain severity phenotype and baseline RBC-EC adhesion profile in SCD subjects -- We will measure the strength of adhesion between single RBCs-ECs from SCD subjects at baseline. Baseline/steady-state adhesion profiles will be compared on an inter-patient level to determine which adhesion profiles correlate most highly with pain severity phenotype. Assess the association of VOE severity with changes in RBC-EC adhesion from baseline to VOE onset. We will measure the change in strength of adhesion between single RBCs-ECs from baseline to VOE onset. Changes in adhesion will be compared on an inter-patient level to determine whether relative changes in adhesion profile at VOE onset correlate with VOE severity. Test the ex vivo effect of targeted pharmacotherapy on the RBC-EC adhesion profile of SCD subjects -- We will measure (at baseline and at VOE onset) the ex vivo inhibitory effect of two known RBC-EC adhesion blockers (propranolol and abciximab) to identify patient-specific anti-adhesive therapeutic signatures.
IRB No. 14-136CS-6.2 (Dr. Biree Andemariam, PI): Hemoglobinopathies and Bone Health
This research study has two purposes. The first purpose is to determine whether having sickle cell trait is a risk factor for the development of bone thinning at an earlier age than expected. Nearly 10% of African Americans carry sickle cell trait and most of them are unaware of it. African Americans are less likely to develop thin bones than whites, but if they sustain a bone fracture, they are more likely to die from it. We believe having sickle cell trait may lead to bone thinning and predispose a subset of African Americans to dangerously thin bones. The second purpose is to try to understand why individuals with sickle cell disease have thinner bones than healthy individuals do. Doctors have already discovered that people with sickle cell disease have very thin bones, but they have not determined why. Our study will try to identify whether the bone thinning is from the body not making enough bone or from the body losing bone once it is made.
IRB No. 17-193C-6.2 (Dr. Biree Andemariam, PI): Measures of Functional Ability in Adults with Sickle Cell Disease
This study is a prospective, clinical/translational research pilot study using a web-based, daily survey. Pain in adults with sickle cell disease (SCD) is unique in that patients often experience acute and chronic pain simultaneously. Numerical rating scales are often unhelpful in the measurement of this type of pain as patients tend to report high pain scores despite noted variations in functional ability. This pattern of functional improvement with continued report of high pain intensity scores is common in patients with recurrent and chronic pain. A functional assessment tool that can reflect functional changes over brief time periods (days) is necessary to 1) allow for the examination of the impact of acute pain on usual function, 2) investigate the extent to which acute pain symptoms create a burden for patients and caretakers, 3) use as an outcome measure that would allow for objective measurement of changes in functioning as the result of acute pain interventions, and 4) study individual differences in functioning within specific patient groups. We have previously developed the YAPFAQ, a measure of acute functional ability in youth with sickle cell disease. No tool for measurement of daily functional ability in adults with SCD exists. The aim of this project is to provide preliminary data on item content for an adult acute functional ability tool, while examining the impact of other variables such as pain, mood and sleep on daily function in individuals with SCD. We propose to complete a pilot study of 40 adults between the ages of 21-40 years with SCD. Each adult will access an online survey daily for 30 days to report 20-30 items regarding their functional ability, sleep, mood and pain. Participants will access the daily survey through any standard web-browser using REDCap and complete the survey between 6pm-10pm each day.
IRB No. 18-036S-6.2 (Dr. Biree Andemariam, PI): Development of Novel Tools to Treat Vaso-Occlusive Pain in Sickle Cell Disease
This study is a prospective, clinical/translational research study with both long term and immediate goals. The long-term goals of this project are two-fold: (i) to quantitatively understand how the adhesive cellular interaction between blood cells and the endothelium can be modified to prevent VOE; (ii) To create simple point-of-care diagnostic tests that will indicate the risk of VOE onset. Our central hypothesis is that the onset of VOE is temporally-related to an increase in blood adhesion and viscosity that can be reversed with anti-adhesion therapy. The immediate goals of this project are to (1) measure the relationship between steady-state SS-RBC--endothelium adhesion and VOE frequency, and identify changes in SS-RBC--endothelium adhesion during VOE onset, (2) demonstrate an ex vivo effect of anti-adhesive therapy on SS-RBC--endothelium adhesion that directly or indirectly targets the cAMP-PKA pathway, and (3) develop simple a single-use microfluidics device capable of indicating the risk for VOE. Atomic force microscope (AFM) and microfluidics will be used to measure adhesion of endothelial proteins to human SS-RBCs isolated from SCD patients at steady-state (no VOE) and at VOE onset. AFM allows specific quantification at the single molecule level of both the number and strength of protein-protein binding events on the RBC surface. Microfluidics allow for high throughput screening. To achieve our goals, we will complete the following specific aims: Aim 1: Determine the relationship between (1) steady-state SS-RBC adhesion and frequency of VOEs and (2) changes in SS-RBC adhesion level and onset of VOEs. Aim 2: Measure the ex vivo effect of pharmacologic blockade of receptor--ligand adhesion in the B-adrenergic system. Aim 3: Design, fabricate, and validate a simple, inexpensive, single-use microfluidics device coupled with a smart-phone kit and software application that will indicate the risk for VOE onset. Our expected outcomes and accomplishments are to (1) identify a relationship between enhanced SS-RBC adhesion and VOE onset, (2) identify therapies capable of limiting the onset and duration of VOEs and (3) create a single-use microfluidics device capable of indicating the risk of VOE onset. This has the potential to impact the development of needed treatments to prevent and reverse VOEs in millions of individuals with SCD worldwide. We will enroll 5 eligible subjects with SCD and 5 healthy controls over a three-year period. During this time, each SCD subject will donate 5 baseline blood samples to ensure we establish a true baseline. Baseline blood samples will be collected periodically during routine clinic visits over the three year study enrollment; at this time, subjects will donate 12 cc of blood. SCD subjects will also document when a painful vaso-occlusive episode (VOE) occurs and will donate a total of 3-4 VOE blood samples over the three year study period. During each VOE blood draw, SCD subjects will donate 12cc of blood. The initial VOE blood sample must be obtained within 48 hours of the VOE onset. Subsequent samples can be obtained in the days following VOE onset or at the time of a new VOE episode. Healthy controls will donate 12 cc of blood on three occasions, with each blood draw being at least one month apart. Blood will be analyzed for CBC/differential, hemoglobin electrophoresis, epinephrine levels, RBC adhesion, and blood viscosity. With this approach, we will test the hypothesis that there is a relationship between steady-state SS-RBC adhesion and frequency of VOEs (Specific Aim #1). SS-RBC adhesion at VOE onset will be compared to steady-state in order to test the hypothesis that enhanced SS-RBC adhesion mediates VOE (Specific Aim #1). Utilizing blood collected from subjects with SCD during steady-state and within 48 hours of VOE onset, we will measure the adhesion of SS-RBCs to the endothelial ligands.
IRB No. 19-148-2 (Dr. Biree Andemariam, PI): An Open-label Extension Study of IMR-687 in Adult Patients with Sickle Cell Anemia (Homozygous HbSS or Sickle-ß0 Thalassemia) Who Participated in Study IMR-SCD-102
Study Title:An Open-label Extension Study of IMR-687 in Adult Patients with Sickle Cell Anemia (Homozygous HbSS or Sickle-B0 Thalassemia) Who Participated in Study IMR-SCD-102 Background: With a neonatal incidence of 294,000 to 330,000 patients worldwide (Piel 2013), SCA is a rare inherited disorder of red blood cells (RBCs) that is both serious and life threatening. The most common manifestations of SCA include vaso-occlusive crisis, chronic and acute severe pain, acute chest syndrome, stroke, priapism, acute anemia (particularly from aplastic crisis and splenic sequestration), increased susceptibility to infection, and progressive damage to major organs including the spleen, brain, kidney, heart, lung, skin, retina, vestibular cochlear systems, and bone. In developed countries where there is prenatal Screening and wide spread access to prophylactic and acute interventions, the median age of death remains in the 40s to 50s though many patients succumb to the disease much earlier (Platt 1994; Lanzkron 2013; Paulukonis 2016). Rationale for the study:Study IMR-SCD-102-EXT is an extension of Study IMR-SCD-102. During the extension, IMR687 100 mg will be administered orally once daily. Since Study IMR-SCD-102 is the first study in patients with SCA, an extension will provide long-term safety and tolerability data for these subjects. In addition, long-term pharamcodynamic (PD) and efficacy data will be collected. Study design: Patients are eligible for this open-label extension study immediately following the End-of-Study visit for Study IMR-SCD-102 (i.e., approximately 30 days after the last dose of study drug in the Phase 2a study). Following screening assessments to determine continued eligibility, patients will be enrolled into this extension study. IMR687 100 mg will be administered orally once daily. Patients will return to the study site for visits at week 1, and months 1, 4, 8, and 12 during the first year. Thereafter, patients will return to the study site every 6 months during years 2, 3, and 4. Telephone-based check-ins may be performed on weeks where there are no scheduled assessments or in the event of lack of patient availability for an in-person visit. Safety and concomitant medications will be monitored throughout the study; PD and clinical outcome measures will be performed at selected site visits. Study sample size:Approximately 70 patients currently participating in Study IMR-SCD-102 are expected to be eligible for this long-term extension. Major study intervention:The dose of IMR-687 to be administered in this extensions study is 100 mg per day as a single oral dose. This is the optimum dose expected being tested in the Phase 2a study and is considered to have positive pharmacodynamic effect, based on preclinical modelling and exposures in the FIH study of IMR-687 in healthy volunteers.Pending emerging data from Study IMR-SCD-102, the dose of IMR-687 may be adjusted in this study as appropriate. Main outcome measures/analyses: Primary objectives: To assess the long-term safety and tolerability of IMR-687 in adult patients with sickle cell anemia (SCA), defined as homozygous sickle hemoglobin (HbSS) or sickle-B0 thalassemia, who were previously enrolled in Study IMR-SCD-102. Exploratory objectives: To assess the pharmacodynamic (PD) effects of IMR-687 in adult patients with SCA who were previously enrolled in Study IMR-SCD-102. To assess the potential efficacy of IMR-687 on SCA-related clinical outcome measures in adult patients with SCA who were previously enrolled in Study IMR-SCD-102.