Phase 2 Study of MP4CO to Treat Vaso-occlusive Sickle Crisis
NCT ID: NCT01925001
Last Updated: 2013-10-28
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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WITHDRAWN
PHASE2
INTERVENTIONAL
2013-10-31
2015-10-31
Brief Summary
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Patients suffering from a sickle crisis experience severe pain and are at risk of stroke, heart attack or even death. Current therapy is limited to hydration and symptomatic pain relief. The administration of MP4CO as an adjunct treatment to standard therapy may alleviate pain associated with a sickling crisis and potentially reduce the severity and duration of a crisis. This may shorten the time in hospital and potentially improve the quality of life for patients with sickle cell anemia.
Detailed Description
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MP4CO is designed as an ischemic rescue therapy to deliver non-toxic levels of CO, to provide an immediate metabolic signal to cells to help reverse red cell sickling, and to reduce inflammation.
Previously published studies provide a foundation to postulate that MP4CO might have the appropriate properties for treatment or reversal of an acute sickling crisis. The initial release of CO from MP4CO is predicted to have a beneficial effect including immediate stabilization of Hb S to prevent further red cell polymerization and reverse existing sickling, dilation of capillaries to enhance tissue perfusion, and anti-inflammatory cell-signalling properties. The subsequent circulation of the MP4 molecule as an oxygen therapeutic (after converting to MP4OX following oxygenation in the lungs) will help to 1) preferentially oxygenate ischemic tissue, 2) reverse partially sickled red cells, and 3) improve perfusion and oxygenation of local tissues to potentially ameliorate the painful crisis caused by sickling of red cells. In addition, MP4CO has enhanced chemical stability, which enables storage at room temperature.
Conditions
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Keywords
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
TRIPLE
Study Groups
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MP4CO
Escalating doses of MP4CO, administered intravenously
MP4CO
43 mg/mL pegylated carboxyhemoglobin \[≥ 90% CO hemoglobin saturation\] in physiological acetate electrolyte solution
Sodium chloride solution
Normal saline (0.9% Sodium Chloride Injection USP)administered intravenously
Sodium chloride solution
Normal saline solution (0.9% Sodium Chloride Injection USP)
Interventions
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MP4CO
43 mg/mL pegylated carboxyhemoglobin \[≥ 90% CO hemoglobin saturation\] in physiological acetate electrolyte solution
Sodium chloride solution
Normal saline solution (0.9% Sodium Chloride Injection USP)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Diagnosis of SCD (known HbSS or HbSß0)
* Sixteen years of age or older
* Prior history of at least one VOC requiring hospitalization within the last 24 months
Exclusion Criteria
* History of overt stroke or cerebral vascular accident within the previous 12 months
* Remained in the hospital for ≥2 weeks (14 days) for VOC management within the previous 6 months
* Known pulmonary hypertension based on an estimated tricuspid regurgitant jet velocity (TRJV) \>2.90 m/s or definitive diagnosis by prior right heart catheterization
* Baseline SaO2 level by pulse oximetry \<92% on room air
* Systemic hypertension (baseline systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 90 mmHg)
* History of myocardial infarction, myocardial ischemia, or angina
* On a chronic red blood cell transfusion therapy program (simple or exchange)
* Renal dysfunction presenting with a GFR\<60 mL/min/1.73m
* Any diagnosis of a concurrent chronic debilitating disease that may affect the completion of the study or results of the study as determined by the investigator
* Currently enrolled in any other investigational treatment study
* Significant substance abuse.
* Known to have HIV, active hepatitis B, or C infection, or active tuberculosis
16 Years
ALL
No
Sponsors
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Sangart
INDUSTRY
Responsible Party
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Principal Investigators
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Tania Small, MD
Role: STUDY_DIRECTOR
Sangart, Inc., San Diego, CA
Swee Lay Thein, MD
Role: PRINCIPAL_INVESTIGATOR
King's College Hospital NHS Trust
Locations
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Salmaniya Medical Complex
Manama, , Bahrain
University Hospital Brugmann
Brussels, , Belgium
Rio de Janerio Instituto Estadual de Hematologie
Rio de Janerio, , Brazil
Hôpital Henri Mondor
Créteil, , France
Georges Pompidou European University Hospital
Paris, , France
American Univ. of Beirut Medical Center
Beirut, , Lebanon
Univ. Medical Center Rizk Hospital
Beirut, , Lebanon
Academic Medical Center
Amsterdam, , Netherlands
Cornell Medical City
Doha, , Qatar
Cukurova University Medical Facilty
Adana, , Turkey (Türkiye)
Mersin University Medical Faculty
Mersin, , Turkey (Türkiye)
Guys Hospital
London, , United Kingdom
King's College Hospital
London, , United Kingdom
Queen Mary Hospital
London, , United Kingdom
Countries
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References
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Vandegriff KD, Young MA, Lohman J, Bellelli A, Samaja M, Malavalli A, Winslow RM. CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats. Br J Pharmacol. 2008 Aug;154(8):1649-61. doi: 10.1038/bjp.2008.219. Epub 2008 Jun 9.
Vandegriff KD, Bellelli A, Samaja M, Malavalli A, Brunori M, Winslow RM. Kinetics of NO and O2 binding to a maleimide poly(ethylene glycol)-conjugated human haemoglobin. Biochem J. 2004 Aug 15;382(Pt 1):183-9. doi: 10.1042/BJ20040156.
Tsai AG, Vandegriff KD, Intaglietta M, Winslow RM. Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics. Am J Physiol Heart Circ Physiol. 2003 Oct;285(4):H1411-9. doi: 10.1152/ajpheart.00307.2003. Epub 2003 Jun 12.
Cole RH, Vandegriff KD. MP4, a vasodilatory PEGylated hemoglobin. Adv Exp Med Biol. 2011;701:85-90. doi: 10.1007/978-1-4419-7756-4_12.
Vandegriff KD, Malavalli A, Mkrtchyan GM, Spann SN, Baker DA, Winslow RM. Sites of modification of hemospan, a poly(ethylene glycol)-modified human hemoglobin for use as an oxygen therapeutic. Bioconjug Chem. 2008 Nov 19;19(11):2163-70. doi: 10.1021/bc8002666.
Svergun DI, Ekstrom F, Vandegriff KD, Malavalli A, Baker DA, Nilsson C, Winslow RM. Solution structure of poly(ethylene) glycol-conjugated hemoglobin revealed by small-angle X-ray scattering: implications for a new oxygen therapeutic. Biophys J. 2008 Jan 1;94(1):173-81. doi: 10.1529/biophysj.107.114314. Epub 2007 Sep 7.
Tsai AG, Cabrales P, Manjula BN, Acharya SA, Winslow RM, Intaglietta M. Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers. Blood. 2006 Nov 15;108(10):3603-10. doi: 10.1182/blood-2006-02-005272. Epub 2006 Jul 20.
Vandegriff KD, McCarthy M, Rohlfs RJ, Winslow RM. Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated. Biophys Chem. 1997 Nov;69(1):23-30. doi: 10.1016/s0301-4622(97)00079-3.
Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012 Nov 1;120(18):3647-56. doi: 10.1182/blood-2012-04-383430. Epub 2012 Aug 24.
Belcher JD, Young M, Chen C, Nguyen J, Burhop K, Tran P, Vercellotti GM. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood. 2013 Oct 10;122(15):2757-64. doi: 10.1182/blood-2013-02-486282. Epub 2013 Aug 1.
Belcher JD, Mahaseth H, Welch TE, Otterbein LE, Hebbel RP, Vercellotti GM. Heme oxygenase-1 is a modulator of inflammation and vaso-occlusion in transgenic sickle mice. J Clin Invest. 2006 Mar;116(3):808-16. doi: 10.1172/JCI26857. Epub 2006 Feb 16.
Bilban M, Haschemi A, Wegiel B, Chin BY, Wagner O, Otterbein LE. Heme oxygenase and carbon monoxide initiate homeostatic signaling. J Mol Med (Berl). 2008 Mar;86(3):267-79. doi: 10.1007/s00109-007-0276-0. Epub 2007 Nov 22.
Piantadosi CA, Withers CM, Bartz RR, MacGarvey NC, Fu P, Sweeney TE, Welty-Wolf KE, Suliman HB. Heme oxygenase-1 couples activation of mitochondrial biogenesis to anti-inflammatory cytokine expression. J Biol Chem. 2011 May 6;286(18):16374-85. doi: 10.1074/jbc.M110.207738. Epub 2011 Mar 18.
Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore). 2005 Nov;84(6):363-376. doi: 10.1097/01.md.0000189089.45003.52.
Related Links
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Sangart, Inc. (Sponsor home page)
Other Identifiers
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SCD-206
Identifier Type: -
Identifier Source: org_study_id