Pain, Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease, Pain, Immune Globulin
Brief summary
The purpose of this study is to determine whether Intravenous Immunoglobulin (IVIG) is safe and effective in the acute treatment of pain crises in sickle cell disease. Funding Source: Food and Drug Administration (FDA), Office of Orphan Products Development (OOPD)
Detailed description
Patients will be randomized to a single dose of IVIG versus normal saline placebo during an uncomplicated pain crisis. Length of vaso-occlusive crisis (VOC) and other secondary endpoints will be monitored. Phase I: To determine the tolerability and obtain preliminary data on the clinical efficacy of IVIG treatment in a randomized, double-blind, placebo-controlled, dose escalation Phase I clinical study of sickle cell disease patients, ages 12-65, admitted for acute vaso-occlusive crisis. Phase II: To evaluate the effect of a single dose of 400mg/kg of intravenous (IV) Gamunex on length of VOC in subjects 6-13.99 years of age (initially 8-65 years of age, see "NOTES/CLARIFICATION below) hospitalized for sickle cell VOC in a randomized, double blind placebo-controlled Phase II trial. To further evaluate safety of a single dose of 400mg/kg of IV Gamunex in subjects 6-65 years of age hospitalized for sickle cell VOC. NOTES/CLARIFICATION: The following is a timeline of the 'evolution' of the required Age Range as per eligibility criteria for this study: Initial Age Range: 8-65 years of age Effective 1/2/2013: 12-65 years of age Effective 3/31/2015: 8-21 years of age Effective 6/22/2018: 8-13 years of age Effective 7/11/2019: 6-13.99 years of age
Interventions
DRUGImmune Globulin Intravenous (IVIG)
A single dose of intravenous immune globulin administered within 24 hours of hospital presentation. The maximum dose in Phase I was 800 mg/kg. The dose for Phase II is 400mg/kg.
OTHERNormal saline
A single dose of normal saline administered within 24 hours of hospital admission for uncomplicated pain crisis.
Sponsors
Albert Einstein College of Medicine
Food and Drug Administration (FDA)
Case Western Reserve University
Grifols Therapeutics LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
1:1 randomization
Eligibility
Sex/Gender
ALL
Age
6 Years to 13 Years
Healthy volunteers
No
Inclusion criteria
Each subject must fulfill each of the following Inclusion/
Exclusion criteria
at screening and continue to fulfill these criteria prior to dosing: Inclusion Criteria: * Documented Sickle Cell Disease (SS or S-β thalassemia genotype) * Age 12-65 years for Phase 1 (Completed), 6-13.99 years for Phase 2 (Ongoing) * Normal stroke risk as assessed by transcranial Doppler (TCD). A normal TCD in subjects 16 years of age and younger within the year prior to study drug administration are required * Uncomplicated acute vaso-occlusive crisis requiring hospital admission and parenteral narcotic analgesics * If prescribed Voxelotor: Consistent daily use of voxelotor in the past week AND able to continue Voxelotor inpatient OR no reported use in prior week
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Length of vaso-occlusive crisis (VOC) | Number of days from time of presentation to emergency room to end of crisis, average 4 days and maximum 30 days | Length (duration) of vaso-occlusive crisis as measured from the time of presentation to the emergency room to end of VOC defined as 12 hours from the last dose of parenteral opioid analgesia for the treatment of VOC prior to hospital discharge. Group results will be summarized in number of days using univariate statistics. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Opioid Use | From study drug infusion to end of crisis, average 4 days and maximum 30 days | The total intravenous morphine equivalent use from the end of infusion to discharge will be compared between the IVIG and placebo group. This will require conversion of total amount of different opioids to the equivalent amounts of IV morphine in milligrams. Standard tables for equianalgesic opioid dosing will be used for these conversions. These tables account for opioid type, route of administration, and incomplete cross-tolerance, as needed, and are adjusted for body weight. Group results will be summarized in milligrams of opioid per kilogram of body weight (mg/kg) using univariate statistics. |
| Time to end of vaso-occlusive crisis | Number of days from start of study drug infusion to end of crisis, average 4 days and maximum 30 days | Time to end of vaso-occlusive crisis as measured from start of study drug infusion to end of VOC end of VOC defined as 12 hours from the last dose of parenteral opioid analgesia for the treatment of VOC prior to hospital discharge. Group results will be summarized in number of days using univariate statistics. |
| Length of Hospitalization | From admission to discharge, average 4 days and maximum 30 days | Length (duration) of Hospitalization will be summarized by study arm in months/days using univariate statistics. |
| Change in Macrophage-1 Antigen (Mac-1) expression | From Pre-infusion to 24-hours post-infusion | Change in Mac-1 expression levels from prior to infusion to 24 hours following infusion will be assessed by the appropriate in vitro adhesion assay to measure adhesion to cellular surfaces. Mac-1 is a cell surface receptor found on lymphocytes and leukocytes and serves as a marker for binding and adhesion. Mac-1 expression levels increase upon activation by inflammatory stimuli leading to a higher concentration of Mac-1 molecules on the cell's surface. Percentage change in Mac-1 from pre-infusion will be summarized by study arm using univariate statistics. |
| Change in Lactate Dehydrogenase (LDH) levels | From Pre-infusion to 24-hours post-infusion | Change in LDH levels from prior to infusion to 24 hours following infusion will be assessed. Percentage change in LDH concentration (in U/L) from pre-infusion will be summarized by study arm using univariate statistics. While normal LDH ranges vary by age/gender and thresholds have not been established for this study, higher LDH levels may serve as inflammatory biomarkers of hemolysis in patients with sickle cell disease and also be indicators of acute or chronic tissue damage. |
| Change in Hemoglobin (Hb) levels | From Pre-infusion to 24-hours post-infusion | Change in Hb levels from prior to infusion to 24 hours following infusion will be assessed. Percentage change in Hb concentration (in g/dL) from pre-infusion will be summarized by study arm using univariate statistics. While normal Hb ranges vary by age/gender and thresholds have not been established for this study, in patients with sickle cell disease, decreased Hb levels may be indicative of anemia, increased risk of thromboembolic events, and organ and tissue damage. |
| Change in High-sensitivity C-reactive protein (hsCRP) levels | From admission to 24-hours post-infusion, average 4 days | Change in hsCRP levels from admission to 24 hours following infusion will be assessed. Percentage change in hsCRP concentration (in mg/L) from admission will be summarized by study arm using univariate statistics. hsCRP serves a biomarker for inflammation. While normal ranges for hsCRP vary by age/gender and thresholds have not been established for this study, higher hsCRP levels may serve as a laboratory correlate of hospitalizations for pain or vaso-occlusive events in patients with sickle cell disease. |
| Rate of transfer to Intensive Care Unit (ICU) | From admission to discharge, average 4 days and maximum 30 days | The percentage of patients who are admitted to the hospital's ICU for an emergent condition will be summarized by study arm. |
| Diagnosis leading to transfer to the ICU | From admission to discharge, average 4 days and maximum 30 days | Diagnoses leading to transfer to the ICU will be summarized by study arm. |
| Number and type of Transfusions | From study drug infusion to discharge, average 4 days and maximum 30 days | The number and types of intervening packed red blood cell transfusions administered during the study will be summarized by study arm. Types of red blood cell transfusions will be categorized (e.g., acute, intermittent, chronic, simple, exchange) and will be administered as clinically indicated and ordered by the physician in accordance with NIH-NHLBI evidence-based management of sickle cell disease guidelines. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORKerry Morrone, MD
Albert Einstein College of Medicine
Outcome results
None listed