Effect of CER-001 on Atherosclerosis in Acute Coronary Syndrome (ACS) Patients - Efficacy and Safety: The CHI SQUARE Trial

NCT01201837 — Phase 2, Completed, 507 participants, Cerenis Therapeutics, SA

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CHI SQUARE: Can HDL Infusions Significantly Quicken Atherosclerosis Regression? A Phase II, Multi-Center, Double-Blind, Ascending Dose, Placebo-Controlled, Dose-Finding Trial of CER-001 or Placebo in Subjects With Acute Coronary Syndrome

Registry	NCT01201837, acronym CHI SQUARE
Status	Completed
Phase	Phase 2
Study type	Interventional; randomized, parallel, masking: quadruple, treatment
Enrollment	507 (Actual)
Sponsor	Cerenis Therapeutics, SA (Industry)
Conditions	Acute Coronary Syndrome
Interventions	Placebo, CER-001 (Drug)
Dates	start 2011-03-01, primary completion 2012-10-01, completion 2013-03-01, first posted 2010-09-15, last updated 2014-03-03
Locations	47 sites in United States, Canada, France, Netherlands

-Summary

Cardiovascular disease remains the most pressing healthcare issue for developed countries and is becoming so for developing countries. There are a number of chronic therapies available for long-term management of risk. Short term therapies for subjects with an acute event, such as an episode of acute coronary syndrome (ACS), are focused on reperfusion and removing thrombus but most subsequent events are caused by atherosclerotic plaque rupture at a different site. There are no approved therapies that can rapidly reduce the burden of unstable, inflamed plaque in the overall coronary vascular bed. HDL has multiple actions that could lead to atherosclerotic plaque stabilization, such as rapid removal of large quantities of cholesterol from the vasculature, improvement in endothelial function, protection against oxidative damage and reduction in inflammation. This study will assess the effects of CER-001, an ApoA-I-based HDL mimetic, on indices of atherosclerotic plaque progression and regression as assessed by intravascular ultrasound (IVUS) measurements in patients with (ACS).

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+Arms and interventions

Arm	Type	Interventions	Description
Placebo	Placebo comparator	Drug: Placebo
Low Dose	Experimental	Drug: CER-001	CER-001 Low Dose
Mid Dose	Experimental	Drug: CER-001	CER-001 Mid Dose
High Dose	Experimental	Drug: CER-001	CER-001 High Dose

Placebo (Drug): Weekly injection
CER-001 (Drug): Weekly injection

+Outcome measures

Primary outcomes

Change in Total Plaque Volume [Baseline and 3 weeks post final dose]: Absolute change in total plaque volume, as assessed by IVUS, from the baseline measurement to the follow-up taken \~3 weeks following the final dose of study medication (approximately 9 weeks after the baseline assessment)

Secondary outcomes

Percent Change in Plaque Volume [Baseline and 3 weeks post final dose]: Percent change in total plaque volume, as assessed by IVUS, from the baseline measurement to the follow-up taken \~3 weeks following the final dose of study medication (approximately 9 weeks after the baseline assessment)

+Eligibility

Sex: All, ages: any to 75 Years

Inclusion Criteria:

* Male or female less than 75 years of age
* Acute coronary syndrome (acute chest pain and a diagnosis of ST segment elevation myocardial infarction, non-ST elevation myocardial infarction or unstable angina)
* Angiographic evidence of coronary artery disease with suitable "target" coronary artery for IVUS evaluation

Exclusion Criteria:

* Females of child-bearing potential
* Weight >120 kg
* Angiographic evidence of >50% stenosis of the left main artery
* Uncontrolled diabetes (HbA1C>10%)
* Hypertriglyceridemia (>500 mg/dL)
* Congestive heart failure (NYHA class III or IV)
* Ejection fraction <35%
* Uncontrolled hypertension (SBP >180 mm Hg)
* Known major hematologic, renal, hepatic, metabolic, gastrointestinal or endocrine dysfunction

+Locations (47)

Facility	City	Country
Heart Center Research LLC	Huntsville, Alabama	United States
Mayo Clinic - Arizona	Phoenix, Arizona	United States
VA San Diego Health Care Center	San Diego, California	United States
Palm Beach Heart Institute, LLC - Zasa Clinical Research	Boynton Beach, Florida	United States
Heart and Vascular Institute of Florida	Clearwater, Florida	United States
Jacksonville Center for Clinical Research	Jacksonville, Florida	United States
Saint Joseph Research Institute	Atlanta, Georgia	United States
The Care Group, LLC	Indianapolis, Indiana	United States
Suburban Hospital	Bethesda, Maryland	United States
University of Michigan Health System	Ann Arbor, Michigan	United States
Detroit Medical Center (DMC) Cardiovascular Institute	Detroit, Michigan	United States
Cardiac and Vascular Research Center of Northern Michigan	Petoskey, Michigan	United States
Alegent Research Center	Omaha, Nebraska	United States
Buffalo Heart Group	Buffalo, New York	United States
Buffalo Cardiology & Pulmonary Associates	Williamsville, New York	United States
University of North Carolina Medical Center	Chapel Hill, North Carolina	United States
LeBauer Cardiovascular Research Foundation	Greensboro, North Carolina	United States
Sanford Heart Center	Fargo, North Dakota	United States
South Oklahoma Heart Research	Oklahoma City, Oklahoma	United States
Penn Presbyterian Medical Center	Philadelphia, Pennsylvania	United States
Sanford Research / USD	Sioux Falls, South Dakota	United States
Baptist Memorial Hospital	Memphis, Tennessee	United States
Dallas VA Medical Center	Dallas, Texas	United States
MultiCare Health System Research Institute / Cardiac Study Center	Tacoma, Washington	United States
Foothills Medical Centre	Calgary, Alberta	Canada
Victoria Heart Institute Foundation	Victoria, British Columbia	Canada
St. John Health Center	St. John's, Newfoundland and Labrador	Canada
London Health Sciences Center	London, Ontario	Canada
St. Michael's Hospital	Toronto, Ontario	Canada
Centre de Santé et de Services Sociaux de Laval	Laval, Quebec	Canada
Montreal Heart Institute	Montreal, Quebec	Canada
Montreal General Hospital Research Institute	Montreal, Quebec	Canada
Institut Universitaire de Cardiologie et Pneumologie de Québec (IUCPQ)	Québec, Quebec	Canada
CSSS du Nord de Lanaudière	Saint-Charles-Borromée, Quebec	Canada
Centre Hospitalier Régional de Trois-Rivières	Trois-Rivières, Quebec	Canada
Hôpital Cardiologique du Haut-Lévesque	Bordeaux, Pessac Cedex	France
Clinique Pasteur	Toulouse	France
Centre Hospitalier Universitaire de Toulouse Rangueil	Toulouse	France
Onze Lieve Vrouwe Gasthius	Amsterdam, AC	Netherlands
Medisch Centrum Leeuwarden	Leeuwarden, AD	Netherlands
Medisch Centrum Alkmaar	Alkmaar, Amsterdam	Netherlands
Academic Medical Center	Amsterdam, AZ	Netherlands
St. Antonius Ziekenhuis Nieuwegein	Nieuwegein, CM	Netherlands
Maassstadziekenhuis Cardiology Research	Rotterdam, DZ	Netherlands
Catharina Ziekenhuis Eindhoven	Eindhoven, EJ	Netherlands
Medisch Spectrum Twente	Enschede, ER	Netherlands
Canisius Wilhelmina Ziekenhuis	Nijmegen, SZ	Netherlands

+Publications

Nanjee MN, Doran JE, Lerch PG, Miller NE. Acute effects of intravenous infusion of ApoA1/phosphatidylcholine discs on plasma lipoproteins in humans. Arterioscler Thromb Vasc Biol. 1999 Apr;19(4):979-89. doi: 10.1161/01.atv.19.4.979. PMID 10195926
Eriksson M, Carlson LA, Miettinen TA, Angelin B. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans. Circulation. 1999 Aug 10;100(6):594-8. doi: 10.1161/01.cir.100.6.594. PMID 10441095
Spieker LE, Sudano I, Hurlimann D, Lerch PG, Lang MG, Binggeli C, Corti R, Ruschitzka F, Luscher TF, Noll G. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation. 2002 Mar 26;105(12):1399-402. doi: 10.1161/01.cir.0000013424.28206.8f. PMID 11914243
Nieuwdorp M, Vergeer M, Bisoendial RJ, op 't Roodt J, Levels H, Birjmohun RS, Kuivenhoven JA, Basser R, Rabelink TJ, Kastelein JJ, Stroes ES. Reconstituted HDL infusion restores endothelial function in patients with type 2 diabetes mellitus. Diabetologia. 2008 Jun;51(6):1081-4. doi: 10.1007/s00125-008-0975-2. Epub 2008 Apr 4. No abstract available. PMID 18389214
Drew BG, Duffy SJ, Formosa MF, Natoli AK, Henstridge DC, Penfold SA, Thomas WG, Mukhamedova N, de Courten B, Forbes JM, Yap FY, Kaye DM, van Hall G, Febbraio MA, Kemp BE, Sviridov D, Steinberg GR, Kingwell BA. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation. 2009 Apr 21;119(15):2103-11. doi: 10.1161/CIRCULATIONAHA.108.843219. Epub 2009 Apr 6. PMID 19349317
Shaw JA, Bobik A, Murphy A, Kanellakis P, Blombery P, Mukhamedova N, Woollard K, Lyon S, Sviridov D, Dart AM. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ Res. 2008 Nov 7;103(10):1084-91. doi: 10.1161/CIRCRESAHA.108.182063. Epub 2008 Oct 2. PMID 18832751
Waksman R, Torguson R, Kent KM, Pichard AD, Suddath WO, Satler LF, Martin BD, Perlman TJ, Maltais JA, Weissman NJ, Fitzgerald PJ, Brewer HB Jr. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol. 2010 Jun 15;55(24):2727-35. doi: 10.1016/j.jacc.2009.12.067. PMID 20538165
Tardif JC, Gregoire J, L'Allier PL, Ibrahim R, Lesperance J, Heinonen TM, Kouz S, Berry C, Basser R, Lavoie MA, Guertin MC, Rodes-Cabau J; Effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) Investigators. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007 Apr 18;297(15):1675-82. doi: 10.1001/jama.297.15.jpc70004. Epub 2007 Mar 26. PMID 17387133
Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, Halpern S, Crowe T, Blankenship JC, Kerensky R. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003 Nov 5;290(17):2292-300. doi: 10.1001/jama.290.17.2292. PMID 14600188
Results publication: Tardif JC, Ballantyne CM, Barter P, Dasseux JL, Fayad ZA, Guertin MC, Kastelein JJ, Keyserling C, Klepp H, Koenig W, L'Allier PL, Lesperance J, Luscher TF, Paolini JF, Tawakol A, Waters DD; Can HDL Infusions Significantly QUicken Atherosclerosis REgression (CHI-SQUARE) Investigators. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J. 2014 Dec 7;35(46):3277-86. doi: 10.1093/eurheartj/ehu171. Epub 2014 Apr 29. PMID 24780501

+Investigators

Jean-Claude Tardif, MD, Principal investigator, Montreal Heart Institute

My Notes

Public

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