Abciximab (ReoPro) as a Therapeutic Intervention for Sickle Cell Vaso-Occlusive Pain Crisis
| Status: | Recruiting |
|---|---|
| Conditions: | Anemia |
| Therapuetic Areas: | Hematology |
| Healthy: | No |
| Age Range: | 5 - 25 |
| Updated: | 3/16/2015 |
| Start Date: | November 2013 |
| Contact: | William S Ferguson, MD |
| Email: | fergusws@slu.edu |
| Phone: | 314-577-5638 |
The purpose of this study is to determine whether giving abciximab (ReoPro) to children with
sickle cell disease who are hospitalized for acute pain crisis will improve their pain and
shorten the time spent in the hospital, when compared with standard supportive care.
sickle cell disease who are hospitalized for acute pain crisis will improve their pain and
shorten the time spent in the hospital, when compared with standard supportive care.
Sickle cell disease (SCD) is one of the more common genetic diseases worldwide, affecting
approximately 1 in 500 African-Americans and 1 in 1000 Hispanic-Americans. A single amino
acid substitution decreases the solubility of deoxygenated hemoglobin, leading to polymer
formation and subsequent distortion of erythrocyte shape from the normal biconcave disc into
a relatively rigid crescent or sickle shape. Initially reversible, the polymer formation
and shape distortion eventually becomes permanent. Clinical manifestations of sickle cell
disease relate both to increased clearance of these misshapen erythrocytes (causing a
chronic hemolytic anemia) as well as occlusion of small (and sometimes large) blood vessels.
Vaso-occlusive phenomena are responsible for much of the acute morbidity of sickle cell
disease, including episodes of pain resulting from bone infarcts, splenic infarction with a
secondary increased risk of infection, and a relatively high incidence of ischemic stroke
(~10% in the first 2 decades of life). In addition, chronic and cumulative ischemic
episodes contribute to long-term morbidity (including avascular necrosis of bone,
retinopathy, renal insufficiency, and pulmonary hypertension) and a significantly shortened
life span. Vaso-occlusive pain crises often require hospitalization for the administration
of parenteral narcotics; the average duration of hospitalization is 4-5 days, and a
significant proportion of patients experience multiple crises per year. In most episodes,
pain continues to intensify over the first 2-3 days before beginning to abate, suggesting
that there is ongoing extension of tissue damage for some time following initiation of the
episode; also, many patients will develop additional foci of pain even during the course of
hospitalization.
While direct mechanical blockage of small vessels by sickled erythrocytes is undoubtedly an
important factor in vaso-occlusion, there are other secondary phenomena that are likely to
contribute to these episodes, including increased erythrocyte adhesion to the endothelium of
post-capillary venules. SCD patients also exhibit chronic pro-coagulation changes in
soluble clotting factors, as well as increased platelet number and activation. The relative
contribution of these various changes to the pathophysiology of vaso-occlusive crises is
unclear. One published study showed that the antiplatelet drug ticlopidine decreased
frequency, duration, and severity of pain crises in SCD patients, suggesting that the
increase in platelet activation does indeed contribute to vaso-occlusion.
Current therapy for vaso-occlusive pain crises is mostly supportive (maintaining adequate
hydration and oxygenation and administering pain medication). With the possible exception
of exchange transfusion—a procedure with significant potential morbidity—there is no therapy
that directly targets the vaso-occlusion.
Abciximab (ReoPro) is the Fab fragment of the chimeric human-mouse monoclonal antibody 7E3.
It avidly binds to both glycoprotein IIb/IIIa and to integrin αvβ3, and so would potentially
inhibit both erythrocyte binding to vascular endothelial as well as platelet adhesion, thus
targeting two separate mechanisms that are felt to be components of the vaso-occlusive
phenomenon in SCD.
The relatively prolonged course of most pain crises—which typically involves increasing
intensity of pain and often development of new areas of pain over the first few
days—suggests that treatment during the early phases of a crisis might be effective in
ameliorating the course of the episode, resulting not only in decreased acute morbidity but
possibly also in less long-term tissue damage. The study hypothesis is that administration
of abciximab early in the course of a vaso-occlusive sickle cell pain crisis will reduce the
median length of hospitalization without an accompanying increase in bleeding or other
serious complications.
Participants will be randomized in a double blind fashion to receive either abciximab
(ReoPro) or placebo intravenously over 12 hours. Randomization will be stratified by sickle
cell genotype: Sickle Cell Anemia (SS) vs. Sickle-Hemoglobin C Disease (SC). All patients
will receive standard supportive care, including hydration, supplemental oxygen as needed to
maintain oxygen saturation >92%, scheduled use of NSAIDS, and narcotics titrated to effect.
approximately 1 in 500 African-Americans and 1 in 1000 Hispanic-Americans. A single amino
acid substitution decreases the solubility of deoxygenated hemoglobin, leading to polymer
formation and subsequent distortion of erythrocyte shape from the normal biconcave disc into
a relatively rigid crescent or sickle shape. Initially reversible, the polymer formation
and shape distortion eventually becomes permanent. Clinical manifestations of sickle cell
disease relate both to increased clearance of these misshapen erythrocytes (causing a
chronic hemolytic anemia) as well as occlusion of small (and sometimes large) blood vessels.
Vaso-occlusive phenomena are responsible for much of the acute morbidity of sickle cell
disease, including episodes of pain resulting from bone infarcts, splenic infarction with a
secondary increased risk of infection, and a relatively high incidence of ischemic stroke
(~10% in the first 2 decades of life). In addition, chronic and cumulative ischemic
episodes contribute to long-term morbidity (including avascular necrosis of bone,
retinopathy, renal insufficiency, and pulmonary hypertension) and a significantly shortened
life span. Vaso-occlusive pain crises often require hospitalization for the administration
of parenteral narcotics; the average duration of hospitalization is 4-5 days, and a
significant proportion of patients experience multiple crises per year. In most episodes,
pain continues to intensify over the first 2-3 days before beginning to abate, suggesting
that there is ongoing extension of tissue damage for some time following initiation of the
episode; also, many patients will develop additional foci of pain even during the course of
hospitalization.
While direct mechanical blockage of small vessels by sickled erythrocytes is undoubtedly an
important factor in vaso-occlusion, there are other secondary phenomena that are likely to
contribute to these episodes, including increased erythrocyte adhesion to the endothelium of
post-capillary venules. SCD patients also exhibit chronic pro-coagulation changes in
soluble clotting factors, as well as increased platelet number and activation. The relative
contribution of these various changes to the pathophysiology of vaso-occlusive crises is
unclear. One published study showed that the antiplatelet drug ticlopidine decreased
frequency, duration, and severity of pain crises in SCD patients, suggesting that the
increase in platelet activation does indeed contribute to vaso-occlusion.
Current therapy for vaso-occlusive pain crises is mostly supportive (maintaining adequate
hydration and oxygenation and administering pain medication). With the possible exception
of exchange transfusion—a procedure with significant potential morbidity—there is no therapy
that directly targets the vaso-occlusion.
Abciximab (ReoPro) is the Fab fragment of the chimeric human-mouse monoclonal antibody 7E3.
It avidly binds to both glycoprotein IIb/IIIa and to integrin αvβ3, and so would potentially
inhibit both erythrocyte binding to vascular endothelial as well as platelet adhesion, thus
targeting two separate mechanisms that are felt to be components of the vaso-occlusive
phenomenon in SCD.
The relatively prolonged course of most pain crises—which typically involves increasing
intensity of pain and often development of new areas of pain over the first few
days—suggests that treatment during the early phases of a crisis might be effective in
ameliorating the course of the episode, resulting not only in decreased acute morbidity but
possibly also in less long-term tissue damage. The study hypothesis is that administration
of abciximab early in the course of a vaso-occlusive sickle cell pain crisis will reduce the
median length of hospitalization without an accompanying increase in bleeding or other
serious complications.
Participants will be randomized in a double blind fashion to receive either abciximab
(ReoPro) or placebo intravenously over 12 hours. Randomization will be stratified by sickle
cell genotype: Sickle Cell Anemia (SS) vs. Sickle-Hemoglobin C Disease (SC). All patients
will receive standard supportive care, including hydration, supplemental oxygen as needed to
maintain oxygen saturation >92%, scheduled use of NSAIDS, and narcotics titrated to effect.
Inclusion Criteria:
1. Diagnosis of sickle cell disease (Hb SS, HbSC, HbS-β0-thalassemia)
2. Age 5.00 to 24.99 years
3. Pain consistent with vaso-occlusive crisis that meets the criteria for
hospitalization and parenteral narcotics: moderate-severe pain unresponsive to oral
medications (NSAIDS + narcotics) that has no alternative etiology (e.g., trauma)
4. Platelet count >100,000
5. INR <1.2, PTT < 40 seconds
6. Negative urine pregnancy test for females of child-bearing potential, including any
female ≥10 years of age
7. Informed consent by patient (≥18 years of age) or parent (if patient <18 years of
age); assent from patients 12-18 years of age
8. Ability to start drug/placebo infusion within 16 hours of admission
Exclusion Criteria:
1. History of stroke (either ischemic or hemorrhagic)
2. Currently receiving anticoagulation medication (heparin within 1 week, Coumadin
within 3 weeks) or medication with irreversible anti-platelet effect (e.g., aspirin,
ticlopidine) within 14 days
3. Red cell transfusion within 60 days
4. Major surgery within 30 days
5. Treatment with hydroxyurea within 30 days (due to evidence that hydroxyurea can
reverse platelet activation in patients with SCD)
6. Tmax ≥ 102.0o F without concomitant signs of infection, or ≥ 100.4o F with any
finding suggestive of bacterial infection, including acute chest syndrome (fever,
respiratory symptoms, and new infiltrate on chest X-ray)
7. Active internal bleeding
8. Known allergy to abciximab or murine proteins
9. Recent (within 6 weeks) gastrointestinal or genitourinary bleeding of clinical
significance
10. Bleeding diathesis
11. History of vasculitis
12. Intracranial neoplasm, arteriovenous malformation or aneurysm
13. Severe uncontrolled hypertension
14. Patients who previously participated in the study must be excluded due to the
increased risk of severe thrombocytopenia.
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