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IVIG in Acute Ischemic Stroke: A Pilot Study (IVIG/AIS)

This study has been withdrawn prior to enrollment.
(difficult recruitment and new black box warning for IVIG)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01628055
First Posted: June 26, 2012
Last Update Posted: November 11, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
CSL Behring
Information provided by (Responsible Party):
Inova Health Care Services
  Purpose

The purpose of the study is to evaluate the ability of IVIG to affect the rate of progression of brain ischemia, as evidenced by neuroimaging.

The results of an ongoing epidemiological study indicate that patients with primary immunodeficiency (PID) on IVIG replacement therapy have an overall prevalence of stroke that is 5 times less than in the general population. Even more striking is the absence of stroke in IVIG-treated PID patients over 65, while in the same general population age group the stroke prevalence goes up to 8.1%. This suggests that the degree of stroke protection correlates with the length of IVIG treatment, since older PID patients have been treated with IVIG significantly longer than younger ones.


Condition Intervention Phase
Ischemic Stroke Biological: Privigen Other: Normal Saline Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: IVIG in Acute Ischemic Stroke: A Pilot Study

Resource links provided by NLM:


Further study details as provided by Inova Health Care Services:

Primary Outcome Measures:
  • Post-IVIG DWI/PI mismatch measurement [ Time Frame: 3 days ]
    Decrease in the size of post IVIG necrotic area relative to baseline values and percent of penumbra saved, defined by neuroimaging as DWI/PI mismatch.


Secondary Outcome Measures:
  • Favorable clinical outcome [ Time Frame: 90 days ]
    Favorable clinical outcome at Day 90, which requires fulfillment of all three of the following criteria: improvement in NIHSS of 8 points or more from baseline; modified Rankin scale (mRS) score of 0-2 points; and Barthel index (BI) of 75-100

  • Clinical outcome measure by NIHSS [ Time Frame: 3 days ]
    Clinical outcome measured by change in NIHSS scores will be also examined on Day 3

  • Active complement fragment levels [ Time Frame: 90 days ]
    Levels of active complement fragments, C3a, C5a, C5b-9 and C4d at Day 0 and post-IVIG and Day 90.

  • Adverse Events [ Time Frame: 90 days ]
    Incidence in adverse events.


Enrollment: 0
Study Start Date: March 2013
Study Completion Date: September 2013
Estimated Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Privigen
The IVIG preparation to be used is 10% liquid (Privigen). IVIG will be applied at a dose of 1.0g/kg, which is approximately 1/2 of the optimal dose used for other immuno/inflammatory indications. The infusion will start at 0.5 ml/kg/hr for the first 30 minutes, to watch for the signs of hypersensitivity to immunoglobulins, and then increased to 2.5 ml/kg/hr, two times slower than the recommended rate indicated in the product package insert (5 ml/kg/hr). Such a low, single dose has not been associated with hyperviscosity and together with a slow infusion will safeguard against occurrence of adverse events related to IVIG infusions. They will receive a total of 1g/kg and depending on patient's weight, it will take between 3.5 to 4+ hours to infuse that amount.
Biological: Privigen
10% liquid intravenous immunoglobulin at a single dose of 1.0g/kg, run at 0.5ml/kg/hr for the first 30 minutes, then increased to 2.5ml/kg/hr until complete (~3-4 hours depending on weight).
Other Names:
  • IVIg
  • Immune Globulin Intravenous (Human)
  • Immune Globulin Intravenous (Human), 10% Liquid
Placebo Comparator: Normal Saline
The placebo is the normal saline. Since saline solution will be infused at the volume equivalent to that in which the intended dose of immunoglobulin molecules will be delivered, the placebo (comparator) arm will also serve as a control for the volume of fluid infused to the treatment arm participants.
Other: Normal Saline

Normal Saline is a sterile, nonpyrogenic solution for fluid and electrolyte replenishment. It contains no antimicrobial agents. The pH is 5.0 (4.5 to 7.0).

It contains 9 g/L Sodium Chloride with an osmolarity of 308 mOsmol/L and 154 mEq/L Sodium and Chloride.

The infusion will start at 0.5 ml/kg/hr for the first 30 minutes and then increased to 2.5 ml/kg/hr for 3-4 hours.

Other Name: 0.9% Sodium Chloride Solution

Detailed Description:
Two pre-clinical studies demonstrated the effectiveness of IVIG preparations in improving the clinical outcome of stroke and at the same time provided evidence of the role of complement fragments in the pathogenesis of ischemia-induced brain damage. Scavenging of these active fragments by IVIG is the likely mechanism of beneficial effect. In one of these studies CSL's own Privigen preparation was used. Considering that it exhibited in-vitro scavenging abilities more pronounced than several other IVIG preparations, and that its in-vivo scavenging capacity was also proven in a relevant animal model, a need to test this preparation in stroke patients is warranted. In addition, activation of complement and the level of activated fragments in humans seem to correlate with the severity of the disease, making them an ideal therapeutic target.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   45 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Onset of neurological symptoms between 4.5 and 8 hours
  2. Male or Female age 45 -75 years old
  3. Score of 10-15 points on the National Institutes of Health Stroke Scale (NIHSS) with clinical signs suggestive of ischemic stroke
  4. Acute brain ischemia with a distinct penumbra (at least 20%), measured by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI), in the territory of the middle cerebral artery, anterior cerebral artery, or posterior cerebral artery with a hemispheric distribution
  5. Ability and willingness to provide informed consent and comply with study requirements and procedures

Exclusion Criteria:

  1. Eligibility for acute thrombolytic (rtPA) treatment
  2. Normal brain MRI
  3. Transient ischemic attack or rapidly improving neurological symptoms
  4. Previous disability
  5. Hemorrhagic stroke on brain MRI (T2*/SWI)
  6. Ongoing infection defined by clinical and laboratory signs: an evidence-based guideline will be followed to detect infectious complications (in short, physical and laboratory measures including WBC, ESR, hsCRP, PCT, fever, abnormal urine, chest X-ray or positive cultures)
  7. Diagnosis of malignancy
  8. Known sensitivity to any ingredients in the study drug or radiological contrast material
  9. Participation in another clinical trial within the past 30 days
  10. Stroke in the previous 3 months
  11. Chronic liver, kidney or hematological disease
  12. Contraindications to MRI -Brain aneurysm clip, implanted neural stimulator, implanted cardiac pacemaker or defibrillator, cochlear implant, ocular foreign body e.g. metal shavings, other implanted medical devices: (e.g. Swan Ganz catheter) insulin pump, metal shrapnel or bullet.
  13. Diabetes
  14. Hypertension
  15. Females who are pregnant or breastfeeding
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01628055


Locations
United States, Virginia
Inova Health Systems; Inova Fairfax Hospital
Falls Church, Virginia, United States, 22042
Sponsors and Collaborators
Inova Health Care Services
CSL Behring
Investigators
Study Director: Beverly C Walters, MD Inova Health Systems
Study Chair: Milan Basta, MD BioVisions, Inc.
Principal Investigator: Jack Cochran, MD Inova Health Systems
  More Information

Publications:
D'Ambrosio AL, Pinsky DJ, Connolly ES. The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Mol Med. 2001 Jun;7(6):367-82. Review.
Ember JA, Hugli TE. Complement factors and their receptors. Immunopharmacology. 1997 Dec;38(1-2):3-15. Review.
de Boer JP, Wolbink GJ, Thijs LG, Baars JW, Wagstaff J, Hack CE. Interplay of complement and cytokines in the pathogenesis of septic shock. Immunopharmacology. 1992 Sep-Oct;24(2):135-48. Review.
Szalai AJ, van Ginkel FW, Wang Y, McGhee JR, Volanakis JE. Complement-dependent acute-phase expression of C-reactive protein and serum amyloid P-component. J Immunol. 2000 Jul 15;165(2):1030-5.
Van Beek J, Bernaudin M, Petit E, Gasque P, Nouvelot A, MacKenzie ET, Fontaine M. Expression of receptors for complement anaphylatoxins C3a and C5a following permanent focal cerebral ischemia in the mouse. Exp Neurol. 2000 Jan;161(1):373-82.
Lindsberg PJ, Ohman J, Lehto T, Karjalainen-Lindsberg ML, Paetau A, Wuorimaa T, Carpén O, Kaste M, Meri S. Complement activation in the central nervous system following blood-brain barrier damage in man. Ann Neurol. 1996 Oct;40(4):587-96.
Nishino H, Czurkó A, Fukuda A, Hashitani T, Hida H, Karadi Z, Lénárd L. Pathophysiological process after transient ischemia of the middle cerebral artery in the rat. Brain Res Bull. 1994;35(1):51-6.
Figueroa E, Gordon LE, Feldhoff PW, Lassiter HA. The administration of cobra venom factor reduces post-ischemic cerebral injury in adult and neonatal rats. Neurosci Lett. 2005 May 20-27;380(1-2):48-53. Epub 2005 Feb 2.
Arumugam TV, Tang SC, Lathia JD, Cheng A, Mughal MR, Chigurupati S, Magnus T, Chan SL, Jo DG, Ouyang X, Fairlie DP, Granger DN, Vortmeyer A, Basta M, Mattson MP. Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14104-9. Epub 2007 Aug 21.
Széplaki G, Szegedi R, Hirschberg K, Gombos T, Varga L, Karádi I, Entz L, Széplaki Z, Garred P, Prohászka Z, Füst G. Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes. Atherosclerosis. 2009 May;204(1):315-20. doi: 10.1016/j.atherosclerosis.2008.07.044. Epub 2008 Aug 14.
De Simoni MG, Rossi E, Storini C, Pizzimenti S, Echart C, Bergamaschini L. The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q. Am J Pathol. 2004 May;164(5):1857-63.
De Simoni MG, Storini C, Barba M, Catapano L, Arabia AM, Rossi E, Bergamaschini L. Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia. J Cereb Blood Flow Metab. 2003 Feb;23(2):232-9.
Akita N, Nakase H, Kaido T, Kanemoto Y, Sakaki T. Protective effect of C1 esterase inhibitor on reperfusion injury in the rat middle cerebral artery occlusion model. Neurosurgery. 2003 Feb;52(2):395-400; discussion 400-1.
Akita N, Nakase H, Kanemoto Y, Kaido T, Nishioka T, Sakaki T. [The effect of C 1 esterase inhibitor on ischemia: reperfusion injury in the rat brain]. No To Shinkei. 2001 Jul;53(7):641-4. Japanese.
Basta M, Fries LF, Frank MM. High doses of intravenous Ig inhibit in vitro uptake of C4 fragments onto sensitized erythrocytes. Blood. 1991 Jan 15;77(2):376-80.
Basta M, Langlois PF, Marques M, Frank MM, Fries LF. High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance. Blood. 1989 Jul;74(1):326-33.
Basta M, Kirshbom P, Frank MM, Fries LF. Mechanism of therapeutic effect of high-dose intravenous immunoglobulin. Attenuation of acute, complement-dependent immune damage in a guinea pig model. J Clin Invest. 1989 Dec;84(6):1974-81.
Basta M. Modulation of complement-mediated immune damage by intravenous immune globulin. Clin Exp Immunol. 1996 May;104 Suppl 1:21-5.
Basta M, Van Goor F, Luccioli S, Billings EM, Vortmeyer AO, Baranyi L, Szebeni J, Alving CR, Carroll MC, Berkower I, Stojilkovic SS, Metcalfe DD. F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins. Nat Med. 2003 Apr;9(4):431-8. Epub 2003 Mar 3.
Basta M. Ambivalent effect of immunoglobulins on the complement system: activation versus inhibition. Mol Immunol. 2008 Oct;45(16):4073-9. doi: 10.1016/j.molimm.2008.07.012. Epub 2008 Aug 15. Review.
Spycher M, Matozan K, Minnig K, Zehnder R, Miescher S, Hoefferer L, Rieben R. In vitro comparison of the complement-scavenging capacity of different intravenous immunoglobulin preparations. Vox Sang. 2009 Nov;97(4):348-54. doi: 10.1111/j.1423-0410.2009.01217.x. Epub 2009 Jul 27.
Al-Buhairi AR, Jan MM. Recombinant tissue plasminogen activator for acute ischemic stroke. Saudi Med J. 2002 Jan;23(1):13-9. Review.
Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999 Dec 1;282(21):2019-26.
Bennett WR, Yawn DH, Migliore PJ, Young JB, Pratt CM, Raizner AE, Roberts R, Bolli R. Activation of the complement system by recombinant tissue plasminogen activator. J Am Coll Cardiol. 1987 Sep;10(3):627-32.
Széplaki G, Varga L, Laki J, Dósa E, Madsen HO, Prohászka Z, Szabó A, Acsády G, Selmeci L, Garred P, Füst G, Entz L. Elevated complement C3 is associated with early restenosis after eversion carotid endarterectomy. Thromb Haemost. 2006 Oct;96(4):529-34.
Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion. 2006 May;46(5):741-53. Review.
Ahsan N, Palmer BF, Wheeler D, Greenlee RG Jr, Toto RD. Intravenous immunoglobulin-induced osmotic nephrosis. Arch Intern Med. 1994 Sep 12;154(17):1985-7.
Bednarík J, Kadanka Z. [Adverse effects of administration of intravenous human immunoglobulins]. Cas Lek Cesk. 1999 Nov 1;138(21):647-9. Review. Czech.
Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005 Dec;29(3):173-84. Review.
Al-Wahadneh AM, Khriesat IA, Kuda EH. Adverse reactions of intravenous immunoglobulin. Saudi Med J. 2000 Oct;21(10):953-6.
Katz U, Shoenfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus. 2005;14(10):802-8. Review.
Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet. 1992 Mar 14;339(8794):662-4.
Fisher M. Characterizing the target of acute stroke therapy. Stroke. 1997 Apr;28(4):866-72. Review.
Lansberg MG, O'Brien MW, Tong DC, Moseley ME, Albers GW. Evolution of cerebral infarct volume assessed by diffusion-weighted magnetic resonance imaging. Arch Neurol. 2001 Apr;58(4):613-7.

Responsible Party: Inova Health Care Services
ClinicalTrials.gov Identifier: NCT01628055     History of Changes
Other Study ID Numbers: IVIG/AIS-IFH-MB-CSL
First Submitted: June 14, 2012
First Posted: June 26, 2012
Last Update Posted: November 11, 2013
Last Verified: November 2013

Keywords provided by Inova Health Care Services:
IVIg
Acute Ischemic Stroke
Stroke
CVA
Cerebrovascular Accident

Additional relevant MeSH terms:
Stroke
Ischemia
Cerebral Infarction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Immunoglobulins
Antibodies
Immunoglobulins, Intravenous
gamma-Globulins
Rho(D) Immune Globulin
Immunologic Factors
Physiological Effects of Drugs


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