Sickle Cell Disease
Conditions
Keywords
Sickle cell disease, Pain crisis, Acute pain episode, Eptifibatide, Antiplatelet therapy, Safety, Treatment
Brief summary
This study will evaluate the safety of eptifibatide in sickle cell patients and how well it works during the course of painful crises. The overall hypothesis that we seek to test is that increased platelet activation and the resultant inflammatory responses are important contributors to the problems of sickle cell disease. Sickle cell disease has been referred to both as a condition associated with increased risk of blood clots and increased inflammation. A painful crisis represents the most common cli nical problem in sickle cell disease, but the treatment of these crises remains inadequate.
Detailed description
Sickle cell disease has been referred to both as a condition associated with increased risk of blood clots and increased inflammation. Despite the abundant laboratory evidence of abnormal blood clotting and inflammation, the contribution of these changes to the problems experienced by patients with sickle cell disease remains uncertain. In additional to abnormal blood clotting, platelets (small blood cells that help blood clotting) are more activated in sickle cell disease patients compared to healthy patients without this disease. In addition, when sickle cell disease patients experience a painful crisis, there is evidence that the platelet activation and abnormal blood clotting increase even further. Activated platelets release a substance called cluster of designation 40 ligand, which can increase how sticky the lining of blood vessels are and can increase the abnormal blood clotting. The level of cluster of designation 40 ligand is much higher in sickle cell disease patients compared to healthy individuals without this disease. In addition, the levels increase even further when sickle cell patients are experiencing a painful crisis. Painful crisis represent the most common clinical problem in sickle cell disease, and are largely responsible for making the lives of these patients so unpredictable. However, the treatment of these painful crisis remains inadequate, consisting mainly of strong pain medications. In this study, we will evaluate the safety of eptifibatide in sickle cell patients and how well it works during the course of painful crises. At the completion of this trial, we will have an improved understanding of the contribution of platelet activation and inflammation to the problems in sickle cell disease. The overall hypothesis that we seek to test is that increased platelet activation and the resultant inflammatory responses are important contributors to the problems of sickle cell disease. We believe that by decreasing platelet stickiness, and the release of mediators of inflammation and abnormal blood clotting, eptifibatide will affect the clinical course of complications in this disease. If the results from our study support the hypothesis that eptifibatide is safe and effective in this population, we plan on carrying out larger studies to more definitively evaluate the safety of eptifibatide and how well it works in the treatment and/or prevention of painful crises in sickle cell disease.
Interventions
DRUGEptifibatide
Patients randomized to eptifibatide will receive two 180 mcg/kg boluses of eptifibatide 10 minutes apart (i.e., a double bolus), followed by a continuous infusion at 2 mcg/kg/min for 6 hours.
DRUGPlacebo
Patients randomized to the placebo arm will receive a saline solution delivered at a volume and rate identical to that of the active drug.
Sponsors
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 18 and 55 years 2. Have confirmed diagnosis of sickle cell anemia or sickle beta zero thalassemia 3. Have a serum creatinine \</= 1.2 mg/dl 4. Have serum transaminase values \< 3 times upper limits of normal 5. Have a platelet count \>/= 150 x 10\^9/L 6. Have normal baseline coagulation profile 7. Sudden onset of pain involving one or more sites and typical of usual pain episodes 8. Have adequate intravenous access 9. Be able to understand the requirements of the study and be willing to give informed consent 10. Women of child-bearing age must be practicing (and will continue to practice for the course of the study) an adequate method of contraception (oral contraception, depo-provera, bilateral tubal ligation or barrier method)
Exclusion criteria
1. Have a baseline hemoglobin \< 6.0 gm/dl 2. Have a history of major gastrointestinal bleeding or a bleeding diathesis 3. Have an ongoing episode of acute chest syndrome 4. Have a past history of clinically overt stroke(s) 5. Have severe hypertension (systolic blood pressure \> 200mmHg and/or diastolic BP \>110mmHg) not adequately controlled on hypertensive medication 6. Have had major surgery within the six weeks preceding enrollment 7. Are pregnant or breastfeeding 8. Are on chronic anticoagulation or antiplatelet (including non-steroidal anti-inflammatory drugs) therapy 9. Have a history of metastatic cancer 10. Are on a chronic transfusion program or have received a blood transfusion in the prior 8 weeks 11. Have a positive urine toxicology screen for phencyclidine, cocaine or amphetamines. 12. Have a history of alcohol abuse 13. Have received any investigational drugs within the past 4 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1) Major Bleeding Episodes | Up to 35 days | Major bleeding episodes are defined as any episode, such as gastrointestinal bleeding or intracranial bleed that typically leads to hospitalization or other prolonged bleeding requiring a blood transfusion |
| Change in Platelet Count | Up to 35 days | Change in platelet counts occurring anytime from randomization up to day 35 (final follow-up visit). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Eptifibatide on Duration of Acute Pain Episodes | Up to 7 days | The duration of the pain episode will be defined as the time from randomization to termination of the pain episode. The pain episode will be considered terminated when the patient states that the crisis is resolved (defined as being ready to go home on oral analgesics) or all of the following criteria are met: 1. Pain relief (pain scores ≤ 40) maintained for at least 2 consecutive readings (assessed using a visual analog scale with measurements from 0 - 100, where 0 is no pain and 100 is worst imaginable pain). 2. No parenteral analgesics have been administered for at least 12 hours. 3. Ability to walk normally (unless he/she was unable to walk for some other reason prior to the crisis onset). |
| Effect of Eptifibatide on Duration of Hospitalization | Up to 7 days | The duration of hospitalization will be defined as the period from randomization to the time an order for discharge from the hospital is written. |
Countries
United States
Participant flow
Recruitment details
Patients with sickle cell disease, admitted with an acute pain episode, and who met eligibility criteria were approached to participate.
Pre-assignment details
Patient who agreed to participate provided informed consent and were screened for eligibility. Eligible patients were subsequently randomized to treatment with eptifibatide or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Eptifibatide Patients randomized to the eptifibatide arm received two 180 mcg/kg boluses of eptifibatide 10 minutes apart (i.e., a double bolus), followed by a continuous infusion at 2 mcg/kg/min for 6 hours. | 9 |
| Placebo Patients randomized to the placebo arm received a saline solution delivered at a volume and rate identical to that of the active drug. | 4 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Eptifibatide | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 4 Participants | 13 Participants |
| Age Continuous | 30.6 years STANDARD_DEVIATION 8.78 | 34.0 years STANDARD_DEVIATION 12.19 | 31.6 years STANDARD_DEVIATION 9.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 4 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 4 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 9 participants | 4 participants | 13 participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 9 | 3 / 4 |
| serious Total, serious adverse events | 8 / 9 | 2 / 4 |
Outcome results
Primary
1) Major Bleeding Episodes
Major bleeding episodes are defined as any episode, such as gastrointestinal bleeding or intracranial bleed that typically leads to hospitalization or other prolonged bleeding requiring a blood transfusion
Time frame: Up to 35 days
Population: Intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eptifibatide | 1) Major Bleeding Episodes | 0 participants |
| Placebo | 1) Major Bleeding Episodes | 0 participants |
Primary
Change in Platelet Count
Change in platelet counts occurring anytime from randomization up to day 35 (final follow-up visit).
Time frame: Up to 35 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eptifibatide | Change in Platelet Count | 97 x 10^9/L |
| Placebo | Change in Platelet Count | -5 x 10^9/L |
Secondary
Effect of Eptifibatide on Duration of Acute Pain Episodes
The duration of the pain episode will be defined as the time from randomization to termination of the pain episode. The pain episode will be considered terminated when the patient states that the crisis is resolved (defined as being ready to go home on oral analgesics) or all of the following criteria are met: 1. Pain relief (pain scores ≤ 40) maintained for at least 2 consecutive readings (assessed using a visual analog scale with measurements from 0 - 100, where 0 is no pain and 100 is worst imaginable pain). 2. No parenteral analgesics have been administered for at least 12 hours. 3. Ability to walk normally (unless he/she was unable to walk for some other reason prior to the crisis onset).
Time frame: Up to 7 days
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eptifibatide | Effect of Eptifibatide on Duration of Acute Pain Episodes | 3.0 Days |
| Placebo | Effect of Eptifibatide on Duration of Acute Pain Episodes | 3.0 Days |
Secondary
Effect of Eptifibatide on Duration of Hospitalization
The duration of hospitalization will be defined as the period from randomization to the time an order for discharge from the hospital is written.
Time frame: Up to 7 days
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Eptifibatide | Effect of Eptifibatide on Duration of Hospitalization | 3.0 Days |
| Placebo | Effect of Eptifibatide on Duration of Hospitalization | 3.0 Days |