Sickle Cell Disease Clinical Trial
Official title:
A Phase 2 Multi-center, Randomized, Double-blind, Comparator-Controlled Dose Finding Study to Evaluate MP4CO for the Acute Treatment of Vaso-occlusive Crises in Subjects With Sickle Cell Disease
Sickle Cell disease is caused by an inherited hemoglobin disorder. Healthy red blood cells
are discoid and can deform and move through small blood vessels to carry oxygen to all parts
of the body. In Sickle Cell disease, as red blood cells circulate and oxygen is released,
the deoxygenated abnormal Hemoglobin S can begin to polymerize and cause red cells to become
sticky and elongated. These "sickled" red cells are less flexible and will obstruct small
blood vessels and prevent normal red cells from circulating freely, which limits oxygen
delivery to tissues and organs. This is known as a "sickling crisis" or "vaso-occlusive
crisis" and is the leading cause of hospitalization in patients with Sickle Cell disease.
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.
Status | Withdrawn |
Enrollment | 0 |
Est. completion date | October 2015 |
Est. primary completion date | June 2015 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 16 Years and older |
Eligibility |
Inclusion Criteria: - Signed Informed Consent (and assent as required for minors) - 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: - = 5 VOCs within the preceding 6 months requiring Emergency Room (ER) visits or hospital admissions - 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 |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Bahrain | Salmaniya Medical Complex | Manama | |
Belgium | University Hospital Brugmann | Brussels | |
Brazil | Rio de Janerio Instituto Estadual de Hematologie | Rio de Janerio | |
France | Hôpital Henri Mondor | Créteil | |
France | Georges Pompidou European University Hospital | Paris | |
Lebanon | American Univ. of Beirut Medical Center | Beirut | |
Lebanon | Univ. Medical Center Rizk Hospital | Beirut | |
Netherlands | Academic Medical Center | Amsterdam | |
Qatar | Cornell Medical City | Doha | |
Turkey | Cukurova University Medical Facilty | Adana | |
Turkey | Mersin University Medical Faculty | Mersin | |
United Kingdom | Guys Hospital | London | |
United Kingdom | King's College Hospital | London | |
United Kingdom | Queen Mary Hospital | London |
Lead Sponsor | Collaborator |
---|---|
Sangart |
Bahrain, Belgium, Brazil, France, Lebanon, Netherlands, Qatar, Turkey, United Kingdom,
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. Review. — View Citation
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. Epub 2006 Feb 16. — View Citation
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. — View Citation
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. Epub 2007 Nov 22. Review. — View Citation
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. — View Citation
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. — View Citation
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):363-76. — View Citation
Svergun DI, Ekström 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. Epub 2007 Sep 7. — View Citation
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. Epub 2006 Jul 20. — View Citation
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. Epub 2003 Jun 12. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
* Note: There are 14 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Adverse events | Adverse events (AEs) assessed daily through 7 days, and Serious Adverse Events (SAEs) throughout Day 28 follow-up visit | Up to 28 days | Yes |
Other | Urine biomarkers | Urinalysis, and biomarkers to evaluate renal function | Up to 7 days | Yes |
Other | Ambulation | Ability to ambulate assessed by Chair Rise and 50-foot walk tests | Daily up to 7 days | No |
Other | Pain diary | Electronic diary recording of daily pain levels using a visual analogue scale (VAS) | Up to 1 year (on average) | No |
Primary | Duration of hospitalization for treatment of painful vaso-occlusive crisis (VOC) | Time from randomization to resolution of the vaso-occlusive crisis, assessed by evaluation of cessation of opioid analgesia, recovery of ambulation, and/or ready for hospital discharge. | Up to 28 days | No |
Secondary | Pain levels | Proportion of subjects with a pre-defined reduction in pain levels assessed using a visual analogue scale (VAS) | Up to 7 days | No |
Secondary | Readmission to emergency room (ER) | Proportion of subjects with at least one return visit to ER after hospital discharge | Up to 28 days | No |
Secondary | Re-admission to hospital for treatment of VOC | Proportion of subjects re-admitted to hospital for VOC treatment within 7 days after discharge | Up to 28 days | No |
Secondary | Acute Chest Syndrome (ACS) complications | Proportion of subjects with ACS complications | Up to 28 days | Yes |
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