Anemia, Sickle Cell, Sickle Cell Disease
Conditions
Keywords
Sickle cell disease, Anemia, Erythropoietin, Hydroxyurea, Sickle cell anemia
Brief summary
The proposed study is a Phase 1/2 multi-center study evaluating the safety and efficacy of erythropoietin (EPO) in combination with hydroxyurea in the treatment of chronic anemia in patients with sickle cell disease (SCD).
Detailed description
Sickle cell disease (SCD) is a devastating inherited hemoglobin disorder characterized by recurrent episodes of pain and chronic hemolytic anemia. Chronic anemia contributes to multi-organ damage and decreased life expectancy in SCD. However, there are limited treatment options for anemia in SCD. Erythropoietin (EPO) is the standard of care for treatment of anemia related to chronic kidney disease (CKD) and is also used ad hoc in patients with SCD. However, there is limited data on the safety and efficacy of EPO in patients with SCD, especially in combination with hydroxyurea. Therefore, this study aims to treat patients on stable hydroxyurea therapy with subcutaneous EPO, with the goal of assessing the safety of EPO therapy and its effect on chronic anemia in SCD. (Note: Outcome measure changes were in place prior to study initiation.)
Interventions
DRUGHydroxyurea
Hydroxyurea is an orally available antimetabolite medication that has been shown to reduce the frequency of painful crises and acute chest syndrome in adults and children with sickle cell disease. Hydroxyurea treats sickle cell disease by a number of different mechanisms, including increasing the expression of fetal hemoglobin (HbF), which reduces sickling of red blood cells.
Epoetin alfa and its biosimilars are first-generation erythropoiesis-stimulating agents (ESAs), which are recombinant versions of erythropoietin (EPO) produced using recombinant DNA technology. Erythropoietin (EPO) is a glycoprotein hormone, naturally produced mainly in the kidneys in response to hypoxia and stimulates red blood cell production (erythropoiesis) in the bone marrow.
Sponsors
Carnegie Mellon University
American Society of Hematology
Julia Xu
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged ≥ 18 years * Confirmed diagnosis of SCD (HbSS or HbS/β0-thalassemia genotypes) * Screening Hb ≤ 9.0 g/dL * Screening transferrin saturation ≥ 20% and ferritin ≥ 50 ng/mL * Must be on stable-dose hydroxyurea treatment (i.e., no changes in dose within 60 days prior to start of study drug) and plan to continue taking hydroxyurea at the same dose and schedule during the study * If receiving L-glutamine or crizanlizumab, must have been receiving the drug at a stable dose for at least 60 days prior to screening and plan to continue taking the drug at the same dose and schedule during the study
Exclusion criteria
* Participating in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes) and/or planning on undergoing an exchange transfusion during the duration of the study; episodic transfusion in response to worsened anemia or VOC is permitted, but participant should not have received a blood transfusion within 60 days of start of study drug * Received voxelotor or EPO within 30 days of start of study drug * Untreated iron deficiency, or had initiation or change in dose of supplemental iron within 30 days of start of study drug * Ongoing acute illness, infection, or VOC within 2 weeks of start of study drug * Arterial or venous thrombosis within 180 days of start of study drug * Grade 3 hypertension (defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg; medical intervention indicated; more than one drug or more intensive therapy than previously used indicated) on two consecutive measurements * Unstable angina, uncontrolled seizure disorder, or active malignancy * End-stage renal disease requiring hemodialysis * Current pregnancy or breastfeeding * Received active treatment on another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to start of study drug or plans to participate in another investigational drug trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hemoglobin (Hb) Response | Baseline to 12 weeks | Hb response is defined as a Hb increase of ≥ 1.0 g/dL at 12 weeks compared to baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Number of Blood Transfusions Per Year | Baseline to 12 weeks | Annualized number of units of simple red blood cell transfusions received in the 12 months before treatment initiation, compared to during the treatment period |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Left Ventricular End-diastolic Volume as Assessed by Echocardiography | Baseline to 12 weeks; Baseline to 24 weeks | Changes in left ventricular end-diastolic volume |
| Changes in Exercise Capacity as Assessed by 6-minute Walk Test With Modified Borg Dyspnea Scale | Baseline to 12 weeks; Baseline to 24 weeks | Changes in 6-minute walk distance and Modified Borg Dyspnea scale (severity of dyspnea during the 6-minute walk test will be measured on a 10-point scale with 0=nothing at all and 10= maximum severity of breathlessness) |
| Changes in Hemoglobin (Hb) | Baseline to 12 weeks | Mean change in Hb at 12 weeks compared to baseline |
| Changes in Absolute Reticulocyte Count | Baseline to 12 weeks; Baseline to 24 weeks | Changes in absolute reticulocyte count |
| Changes in Tricuspid Valve Regurgitant Jet Velocity as Assessed by Echocardiography | Baseline to 12 weeks; Baseline to 24 weeks | Changes in tricuspid valve regurgitant jet velocity |
| Changes in Renal Function | Baseline to 12 weeks; Baseline to 24 weeks | Changes in serum creatinine (and associated eGFR) |
| Changes in Urine Albumin-to-creatinine Ratio | Baseline to 12 weeks; Baseline to 24 weeks | Changes in urine albumin-to-creatinine ratio |
| Changes in Total and Indirect Bilirubin | Baseline to 12 weeks; Baseline to 24 weeks | Changes in total and indirect bilirubin |
| Changes in Ferritin | Baseline to 12 weeks; Baseline to 24 weeks | Changes in ferritin |
| Changes in Lactate Dehydrogenase | Baseline to 12 weeks; Baseline to 24 weeks | Changes in lactate dehydrogenase |
| Changes in Cardiac Index as Assessed by Echocardiography | Baseline to 12 weeks; Baseline to 24 weeks | Changes in cardiac index |
Countries
Nigeria, United States
Participant flow
Recruitment details
Potential participants will be identified through outpatient hematology clinics at Lagos University Teaching Hospital and UPMC Adult Sickle Cell Clinic. Treating clinicians may refer eligible patients, and study staff may review clinic schedules and electronic health records to identify potentially eligible individuals. IRB-approved recruitment materials may be used, and interested individuals may self-refer by contacting the study team.
Pre-assignment details
Interested individuals will undergo an informed consent process prior to any study-specific procedures. Eligibility will be confirmed through review of medical history, laboratory values, and other inclusion and exclusion criteria. Participants who meet all eligibility criteria will be enrolled and assigned to the study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Erythropoietin Subjects on a stable dose of hydroxyurea will be treated with increasing doses of subcutaneous erythropoietin (EPO) as tolerated for an initial 12 weeks, during which the main safety and efficacy endpoints (including the primary endpoint of hemoglobin response) will be assessed. Subjects may continue on treatment for an additional 12 weeks as clinically indicated, with assessment of additional endpoints at the end of the 24-week study period. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Period | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Erythropoietin |
|---|---|
| Age, Continuous | 30 Year |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Nigeria | 14 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 7 Participants |
| Sickle cell disease genotype Hemoglobin S/beta0-thalassemia | 0 Participants |
| Sickle cell disease genotype Hemoglobin S/beta+-thalassemia | 0 Participants |
| Sickle cell disease genotype Hemoglobin SC disease | 0 Participants |
| Sickle cell disease genotype Hemoglobin SS disease | 16 Participants |
| Sickle cell disease genotype Other | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 17 |
| other Total, other adverse events | 15 / 17 |
| serious Total, serious adverse events | 2 / 17 |
Outcome results
Primary
Percentage of Participants With Hemoglobin (Hb) Response
Hb response is defined as a Hb increase of ≥ 1.0 g/dL at 12 weeks compared to baseline
Time frame: Baseline to 12 weeks
Population: All enrolled participants who have completed baseline and end of treatment testing, regardless of duration of treatment with EPO, will be included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erythropoietin | Percentage of Participants With Hemoglobin (Hb) Response | 15 Participants |
Secondary
Change in Number of Blood Transfusions Per Year
Annualized number of units of simple red blood cell transfusions received in the 12 months before treatment initiation, compared to during the treatment period
Time frame: Baseline to 12 weeks
Population: All enrolled participants who have completed baseline and end-of-treatment (12-week) testing, regardless of duration of treatment with EPO, will be included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Change in Number of Blood Transfusions Per Year | -1.1 Transfusions per year | Standard Deviation 3.7 |
Other Pre-specified
Changes in Absolute Reticulocyte Count
Changes in absolute reticulocyte count
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Cardiac Index as Assessed by Echocardiography
Changes in cardiac index
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Exercise Capacity as Assessed by 6-minute Walk Test With Modified Borg Dyspnea Scale
Changes in 6-minute walk distance and Modified Borg Dyspnea scale (severity of dyspnea during the 6-minute walk test will be measured on a 10-point scale with 0=nothing at all and 10= maximum severity of breathlessness)
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Ferritin
Changes in ferritin
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Hemoglobin (Hb)
Mean change in Hb at 12 weeks compared to baseline
Time frame: Baseline to 12 weeks
Population: All enrolled participants who have completed baseline and end-of-treatment (12-week) testing, regardless of duration of treatment with EPO, will be included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erythropoietin | Changes in Hemoglobin (Hb) | 3.0 g/dL | Standard Deviation 1.6 |
Other Pre-specified
Changes in Lactate Dehydrogenase
Changes in lactate dehydrogenase
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Left Ventricular End-diastolic Volume as Assessed by Echocardiography
Changes in left ventricular end-diastolic volume
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Renal Function
Changes in serum creatinine (and associated eGFR)
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Total and Indirect Bilirubin
Changes in total and indirect bilirubin
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Tricuspid Valve Regurgitant Jet Velocity as Assessed by Echocardiography
Changes in tricuspid valve regurgitant jet velocity
Time frame: Baseline to 12 weeks; Baseline to 24 weeks
Other Pre-specified
Changes in Urine Albumin-to-creatinine Ratio
Changes in urine albumin-to-creatinine ratio
Time frame: Baseline to 12 weeks; Baseline to 24 weeks