Abciximab (ReoPro) as a Therapeutic Intervention for Sickle Cell Vaso-Occlusive Pain Crisis

Lead Sponsor

St. Louis University

Collaborators

Janssen Services, LLC

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

Sickle Cell Disease

, Hb-SS Disease With Vasoocclusive Pain

, Hemoglobin SS Disease With Vasoocclusive Crisis

, Other Sickle Cell Disease With Vaso-Occlusive Pain

, Hemoglobin SS Disease With Crisis

Intervention

Intervention Type

Drug

Intervention Name

Parenteral narcotic

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

Incentive spirometry

Description

Patients will perform incentive spirometry every 2 hours while awake

Arm Group Label

Abciximab

Placebo

Intervention Type

Other

Intervention Name

Supplemental oxygen

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

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

Sickle Cell Pain Crisis

, Abciximab

, Integrins

, Cell Adhesion Molecules

Has Expanded Access

Condition Browse

Anemia, Sickle Cell

Number Of Arms

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

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

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, 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.

ICH GCP | Clinical Trials Registry