Abciximab (ReoPro) as a Therapeutic Intervention for Sickle Cell Vaso-Occlusive Pain Crisis
Abciximab (ReoPro) as a Therapeutic Intervention for Sickle Cell Vaso-Occlusive Pain Crisis
Sponsors
Source
St. Louis University
Oversight Info
Has Dmc
Yes
Brief Summary
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.
Detailed Description
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.
Overall Status
Withdrawn
Start Date
2013-11-01
Completion Date
2015-03-01
Primary Completion Date
2015-03-01
Phase
Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
Duration of hospitalization |
Duration of hospital stay, expected average of 5 days |
Secondary Outcome
Measure |
Time Frame |
Total narcotic dose |
Duration of hospital stay, expected average of 5 days |
Bleeding complications |
From randomization until 10 days following initial discharge from hospital |
Complications (other than bleeding) attributed to study drug |
From randomization until 3 months following initial discharge from hospital |
Readmission rate |
From discharge date until 3 months following initial discharge from hospital |
Conditions
Intervention
Intervention Type
Drug
Intervention Name
Description
Abciximab will be administered as initial bolus of dose of 0.25 mg/kg, delivered via syringe pump over 15 minutes, followed by a continuous infusion of 0.125 microgram/kg/min (max of 10 micrograms/min) infused over the next 12 hours. Infusion to start within 16 hours of admission. All patients will receive standard supportive care measures.
Arm Group Label
Abciximab
Other Name
ReoPro
Intervention Type
Drug
Intervention Name
Description
Inactive placebo will be administered as initial bolus followed by a continuous infusion over the next 12 hours, in syringes and volumes identical with the drug administered in the experimental arm. Infusion to begin within 16 hours of admission. All patients will also receive standard supportive care measures.
Arm Group Label
Placebo
Intervention Type
Other
Intervention Name
Description
intravenous hydration to provide total fluid intake of 1.25-1.5 times maintenance fluid requirements
Arm Group Label
Abciximab
Placebo
Intervention Type
Drug
Intervention Name
Description
Scheduled ibuprofen,~10 mg/kg every 6-8 hours
Arm Group Label
Abciximab
Placebo
Other Name
Advil, Motrin
Intervention Type
Drug
Intervention Name
Description
Parenteral morphine administered by bolus or patient-controlled analgesia to maintain pain control. Hydromorphone or fentanyl will be used in patients who do not tolerate morphine.
Arm Group Label
Abciximab
Placebo
Other Name
morphine
hydromorphone
Dilaudid
fentanyl
Intervention Type
Other
Intervention Name
Description
Patients will perform incentive spirometry every 2 hours while awake
Arm Group Label
Abciximab
Placebo
Intervention Type
Other
Intervention Name
Description
Supplemental oxygen by nasal cannula or mask will be provided if needed to maintain oxygen saturation of 92% or greater.
Arm Group Label
Abciximab
Placebo
Eligibility
Criteria
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.
Gender
All
Minimum Age
5 Years
Maximum Age
25 Years
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
William S Ferguson, MD |
Principal Investigator |
St. Louis University |
Location
Facility |
Cardinal Glennon Children's Medical Center St. Louis Missouri 63104 United States |
Location Countries
Country
United States
Verification Date
2015-03-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Principal Investigator
Investigator Affiliation
St. Louis University
Investigator Full Name
William Ferguson M.D.
Investigator Title
Professor of Pediatrics
Keywords
Has Expanded Access
No
Condition Browse
Number Of Arms
2
Intervention Browse
Mesh Term
Ibuprofen
Fentanyl
Morphine
Hydromorphone
Narcotics
Abciximab
Arm Group
Arm Group Label
Abciximab
Arm Group Type
Experimental
Description
Abciximab will be administered as initial bolus of dose of 0.25 mg/kg, delivered via syringe pump over 15 minutes, followed by a continuous infusion of 0.125 microgram/kg/min (max of 10 micrograms/min) infused over the next 12 hours. Infusion to start within 16 hours of admission.
Patients will receive standard supportive care, including intravenous hydration, supplemental oxygen, incentive spirometry, ibuprofen, and parenteral narcotic pain medications (morphine, hydromorphone or fentanyl)
Arm Group Label
Placebo
Arm Group Type
Placebo Comparator
Description
Inactive placebo will be administered as initial bolus followed by a continuous infusion over the next 12 hours, in syringes and volumes identical with the drug administered in the experimental arm. Infusion to begin within 16 hours of admission.
Patients will receive standard supportive care, including intravenous hydration, supplemental oxygen, incentive spirometry, ibuprofen, and parenteral narcotic pain medications (morphine, hydromorphone or fentanyl)
Firstreceived Results Date
N/A
Why Stopped
Insufficient recruitment
Reference
Citation
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357967
Citation
Dean J, Schechter AN. Sickle-cell anemia: molecular and cellular bases of therapeutic approaches (second of three parts). N Engl J Med. 1978 Oct 12;299(15):804-11.
PMID
692564
Citation
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997 Sep 11;337(11):762-9. Review.
PMID
9287233
Citation
Lane PA. Sickle cell disease. Pediatr Clin North Am. 1996 Jun;43(3):639-64. Review.
PMID
8649903
Citation
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44.
PMID
7993409
Citation
Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991 Jul 4;325(1):11-6.
PMID
1710777
Citation
Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999 Apr 1;340(13):1021-30. Review.
PMID
10099145
Citation
Rees DC, Olujohungbe AD, Parker NE, Stephens AD, Telfer P, Wright J; British Committee for Standards in Haematology General Haematology Task Force by the Sickle Cell Working Party. Guidelines for the management of the acute painful crisis in sickle cell disease. Br J Haematol. 2003 Mar;120(5):744-52.
PMID
12614204
Citation
Hebbel RP. Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle erythrocytes with endothelium. J Clin Invest. 1997 Jun 1;99(11):2561-4. Review.
PMID
9169483
Citation
Kaul DK, Tsai HM, Liu XD, Nakada MT, Nagel RL, Coller BS. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood. 2000 Jan 15;95(2):368-74.
PMID
10627437
Citation
Finnegan EM, Barabino GA, Liu XD, Chang HY, Jonczyk A, Kaul DK. Small-molecule cyclic alpha V beta 3 antagonists inhibit sickle red cell adhesion to vascular endothelium and vasoocclusion. Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H1038-45. Epub 2007 May 4.
PMID
17483236
Citation
Ataga KI, Orringer EP. Hypercoagulability in sickle cell disease: a curious paradox. Am J Med. 2003 Dec 15;115(9):721-8. Review.
PMID
14693325
Citation
Ataga KI, Key NS. Hypercoagulability in sickle cell disease: new approaches to an old problem. Hematology Am Soc Hematol Educ Program. 2007:91-6. Review.
PMID
18024615
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Triple (Participant, Care Provider, Investigator)
Study First Submitted
August 19, 2013
Study First Submitted Qc
August 27, 2013
Study First Posted
August 30, 2013
Last Update Submitted
March 24, 2015
Last Update Submitted Qc
March 24, 2015
Last Update Posted
March 26, 2015
ClinicalTrials.gov processed this data on December 11, 2019
Conditions
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conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.