Clinical trial NCT01757418: Intravenous Gammaglobulin for Sickle Cell Pain Crises
Official title: Phase 1-2 Trial of Gamunex (intravenous Gammaglobulin) for Sickle Cell Acute Pain
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Sickle Cell Disease
Pain
Keywords: Sickle Cell Disease
Pain
Immune Globulin
Lead sponsor: Albert Einstein College of Medicine
Sponsor class: OTHER
Collaborators: name: Food and Drug Administration (FDA)
name: Case Western Reserve University
name: Grifols Therapeutics LLC
First posted: 2012-12-31
Enrollment: 300
Sex: ALL
Minimum age (years): 6
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether intravenous immune globulin 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 VOC and other secondary endpoints will be monitored.

Eligibility 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

Exclusion Criteria:

* Concomitant acute process, including acute chest syndrome, potential serious infection, or clinically significant bleeding
* Fever \> 38.5° C and clinical suspicion of infection
* Serum alanine aminotransferase \>4x Upper Limit of Normal (ULN)
* Serum creatinine ≥1.3 mg/dL (or \> than 95th percentile for age) or \>300 mg/dL protein in spot urinalysis
* Known condition associated with renal dysfunction including but not limited to diabetes mellitus, uncontrolled hypertension, multiple myeloma, and congestive heart failure
* Any clinical evidence of prior stroke
* Prior thromboses or current estrogen use
* Current estrogen use
* Hb \< 5 g/dL or \> 10 g/dL
* Known Immunoglobulin A (IgA) deficiency or known allergy to gamma globulin
* Pregnancy or breastfeeding
* Current participation in another investigational drug study
* Current enrollment in a hypertransfusion program
* Previous participation in current study less than 3 months ago
* Current treatment with chronic transfusion
* Vaccination with a live attenuated virus in the preceding 6 weeks
* Documented history of illicit (e.g., heroin, cocaine) drug abuse
* Subject is otherwise not an appropriate study candidate, in the investigator's judgement, such as concern for opioid addiction or comorbid psychiatric diagnoses that may contribute to secondary gain in prolonged use of opioids or hospital stay
* Greater than 24 hours from time of presentation to the hospital for VOC
* Atrial fibrillation
* Right to left cardiac shunting due to patent foramen ovale or other anatomic cause
* Known magnetic resonance imaging/angiography (MRI/A) evidence of stroke or clinically significant central nervous system (CNS) vasculopathy at any age (Imaging done if clinically indicated)

Primary outcomes:
measure: Length of vaso-occlusive crisis (VOC)
timeFrame: Number of days from time of presentation to emergency room to end of crisis, average 4 days and maximum 30 days
Secondary outcomes:
measure: Total Opioid Use
timeFrame: From study drug infusion to end of crisis, average 4 days and maximum 30 days
measure: Time to end of vaso-occlusive crisis
timeFrame: Number of days from start of study drug infusion to end of crisis, average 4 days and maximum 30 days
measure: Length of Hospitalization
timeFrame: From admission to discharge, average 4 days and maximum 30 days
measure: Change in Macrophage-1 Antigen (Mac-1) expression
timeFrame: From Pre-infusion to 24-hours post-infusion
measure: Change in Lactate Dehydrogenase (LDH) levels
timeFrame: From Pre-infusion to 24-hours post-infusion
measure: Change in Hemoglobin (Hb) levels
timeFrame: From Pre-infusion to 24-hours post-infusion
measure: Change in High-sensitivity C-reactive protein (hsCRP) levels
timeFrame: From admission to 24-hours post-infusion, average 4 days
measure: Rate of transfer to Intensive Care Unit (ICU)
timeFrame: From admission to discharge, average 4 days and maximum 30 days
measure: Diagnosis leading to transfer to the ICU
timeFrame: From admission to discharge, average 4 days and maximum 30 days
measure: Type of Transfusions
timeFrame: From study drug infusion to discharge, average 4 days and maximum 30 days
Other outcomes:
Locations:
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
Study officials:
affiliation: Albert Einstein College of Medicine
name: Deepa G Manwani, M.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chang J, Shi PA, Chiang EY, Frenette PS. Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion. Blood. 2008 Jan 15;111(2):915-23. doi: 10.1182/blood-2007-04-084061. Epub 2007 Oct 11.
citation: Turhan A, Jenab P, Bruhns P, Ravetch JV, Coller BS, Frenette PS. Intravenous immune globulin prevents venular vaso-occlusion in sickle cell mice by inhibiting leukocyte adhesion and the interactions between sickle erythrocytes and adherent leukocytes. Blood. 2004 Mar 15;103(6):2397-400. doi: 10.1182/blood-2003-07-2209. Epub 2003 Nov 20.
citation: Shi PA, Manwani D, Olowokure O, Nandi V. Serial assessment of laser Doppler flow during acute pain crises in sickle cell disease. Blood Cells Mol Dis. 2014 Dec;53(4):277-82. doi: 10.1016/j.bcmd.2014.04.001. Epub 2014 May 21.
citation: Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013 Dec 5;122(24):3892-8. doi: 10.1182/blood-2013-05-498311. Epub 2013 Sep 19.
citation: Manwani D, Chen G, Carullo V, Serban S, Olowokure O, Jang J, Huggins M, Cohen HW, Billett H, Atweh GF, Frenette PS, Shi PA. Single-dose intravenous gammaglobulin can stabilize neutrophil Mac-1 activation in sickle cell pain crisis. Am J Hematol. 2015 May;90(5):381-5. doi: 10.1002/ajh.23956. Epub 2015 Apr 1.
citation: Manwani D, Xu C, Lee SK, Amatuni G, Cohen HW, Carullo V, Morrone K, Davila J, Shi PA, Ireland K, Keenan J, Frenette PS. Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis. Complement Ther Med. 2020 Aug;52:102481. doi: 10.1016/j.ctim.2020.102481. Epub 2020 Jun 9.