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ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE I)

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.
 
ClinicalTrials.gov Identifier: NCT01067820
Recruitment Status : Completed
First Posted : February 12, 2010
Last Update Posted : June 4, 2013
Sponsor:
Collaborator:
The Cleveland Clinic
Information provided by (Responsible Party):
Resverlogix Corp

Brief Summary:
This study is designed to characterize the early effects of ApoA-I synthesis with RVX000222 on coronary atherosclerotic disease when administered to patients with coronary artery disease and have a low HDL-C level, as assessed by Intravascular Ultrasound (IVUS) in addition to standard background therapy.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Drug: RVX000222 Drug: Placebo RVX000222 Phase 2

Detailed Description:
One-third of the US population, almost 80 million adults, have cardiovascular disease and mortality associated with heart disease still remains as a leading cause of death around the world. The major risk factors for cardiovascular disease associated with atherosclerosis is dyslipidemia, characterized by high levels of low density lipoprotein (LDL) and/or low levels of high density lipoprotein (HDL). The widespread use of statins in patients at risk for cardiovascular disease has led to lower LDL levels but has had little effect on HDL levels. HDL has a well established role in atherosclerosis and cardiovascular disease protection. HDL mediates the removal of cholesterol from the atherosclerotic plaques for elimination from the body. The major component of HDL consists of apolipoprotein A-I (ApoA I). Recent intervention studies with synthetic HDL particles and recombinant ApoA-I have shown that HDL has the capacity to reverse coronary atherosclerosis. Increasing ApoA-I is likely to have a favorable effect on atherosclerotic plaque stability and size and on cardiovascular diseases. RVX000222 is a member of a novel class of small molecules that are candidates for the treatment of dyslipidemia by increasing plasma levels of HDL through increased ApoA-I transcription.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 324 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase IIb Multi-center, Double-blind, Randomized, Parallel Group, Placebo-controlled Clinical Trial for the Assessment of Coronary Plaque Changes With RVX000222 as Determined by Intravascular Ultrasound
Study Start Date : September 2011
Actual Primary Completion Date : May 2013
Actual Study Completion Date : June 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: RVX000222, 200 mg daily Drug: RVX000222
capsule, 200 mg, administer with food, 100 mg twice daily 10-12 hrs apart, 26 weeks

Placebo Comparator: Placebo Drug: Placebo RVX000222
capsule, administer with food, twice daily 10-12 hrs apart, 26 weeks




Primary Outcome Measures :
  1. The nominal change in percent atheroma volume (PAV) from baseline to 26 weeks postrandomization, as determined by intravascular ultrasound (IVUS) within the RVX000222 treated group. [ Time Frame: baseline to 26 weeks postrandomization ]
    To evaluate the effect of RVX000222 on the change in burden of coronary atherosclerosis, as measured by percent atheroma volume (PAV), in patients with coronary artery disease and a low level of HDL-C requiring angiography for a clinical indication.


Secondary Outcome Measures :
  1. Nominal change in percent atheroma volume (PAV), from baseline to 26 weeks postrandomization, as determined by intravascular ultrasound (IVUS) within the RVX000222 treated group compared to placebo. [ Time Frame: baseline to 26 weeks postrandomization ]
    To evaluate the effect of RVX000222 on the change in total atheroma volume (TAV), changes in the 10-mm most diseased artery sub-segment containing the most amount of disease and the percentage of patients who demonstrate regression of coronary atherosclerosis.

  2. Nominal change in total atheroma volume (TAV) from baseline to 26 weeks postrandomization, as determined by intravascular ultrasound (IVUS) in the RVX000222 treated group as well as compared to placebo. [ Time Frame: baseline to 26 weeks postrandomization ]
    To evaluate the effect of RVX000222 on the change in total atheroma volume (TAV), changes in the 10-mm most diseased artery sub-segment containing the most amount of disease and the percentage of patients who demonstrate regression of coronary atherosclerosis.

  3. Nominal change in total atheroma volume (TAV) for the 10-mm sub-segment with the greatest disease burden at baseline, within the RVX000222 treated group as well as compared to placebo. [ Time Frame: baseline to 26 weeks postrandomization ]
    To evaluate the effect of RVX000222 on the change in total atheroma volume (TAV), changes in the 10-mm most diseased artery sub-segment containing the most amount of disease and the percentage of patients who demonstrate regression of coronary atherosclerosis.

  4. Proportion of patients with regression of coronary atherosclerosis, defined as a change in percent atheroma volume (PAV) from baseline to 26 weeks of less than zero (i.e. any reduction in PAV). [ Time Frame: baseline to 26 weeks postrandomization ]
    To evaluate the effect of RVX000222 on the change in total atheroma volume (TAV), changes in the 10-mm most diseased artery sub-segment containing the most amount of disease and the percentage of patients who demonstrate regression of coronary atherosclerosis.

  5. Percent change from baseline in HDL-C, ApoA-I, and HDL-subclasses at various time points within the RVX000222 treated group as well as compared to placebo. [ Time Frame: Week 14 and 26 ]
    To evaluate the effect of RVX000222 on biomarkers (HDL-C, ApoA-I, HDL-subclasses) at various time points.

  6. Incidence of adverse events by treatment group, including major adverse cardiac events (MACE) (death, MI, stroke, coronary revascularization, hospitalization for ACS or heart failure). [ Time Frame: Continuous ]
    To evaluate the safety and tolerability of RVX000222.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male and female patient's >/= 18 years of age who are scheduled to undergo coronary angiography for a clinical indication.
  2. Women of child-bearing potential, that is, women not surgically sterilized and between menarche and 1 year post menopause, must test negative for pregnancy at the time of enrollment based on a serum pregnancy test and agree to use a reliable method of birth control (for example, use of oral contraceptives or Norplant; a reliable barrier method of birth control (diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices; partner with vasectomy; or abstinence) during the study and for one month following the last dose of study drug.
  3. Current (Local lab within 60 days prior to Visit 1). HDLC of </= 45 mg/dL (1.2 mmol/L) for females and HDLC of </=40 mg/dL (1.0 mmol/L) for males.
  4. In the opinion of the investigator patients currently not on statin therapy will be able to start either atorvastatin (10 mg, 20mg or 40mg) or rosuvastatin (5mg, 10mg or 20 mg) at Visit 1.
  5. In the opinion of the investigator patients currently on statin therapy other than atorvastatin (10 mg, 20mg or 40mg) or rosuvastatin (5mg, 10mg or 20 mg) can be switched to rosuvastatin (5mg, 10mg or 20 mg) at Visit 1.
  6. Patients must meet all of the following criteria at the qualifying coronary catheterization procedure:

    A. Entire Coronary Circulation: Angiographic evidence of coronary heart disease as defined by at least one lesion in any of the three major native coronary arteries that has >20 percent reduction in lumen diameter by angiographic visual estimation or prior history of PCI. This vessel need not be the target coronary artery for IVUS. Any vessel with previous PCI may not be used as the target coronary artery.

    B. Left Main Coronary Artery: Must not have a >50 percent reduction in lumen diameter by visual angiographic estimation.

    C. Target Coronary Artery for IVUS: Must be accessible to the IVUS catheter. Must have a <50 percent reduction in lumen diameter by angiographic visual estimation throughout a segment of at least 40 mm in length (the "target segment"). A lesion of up to 60 percent stenosis is permitted, distal to the target segment. A single branch of the "target vessel" may have a narrowing up to but <70 percent by visual estimation, as long as the target segment contains no lesion >50 percent, provided that the branch in question is not a target for PCI or CABG. Has not undergone prior percutaneous coronary intervention or coronary artery bypass graft surgery. The target vessel is not currently a candidate for intervention or a likely candidate for intervention over the next 6 months. The target vessel may not be a bypass graft. The target vessel may not be a bypassed vessel. The target vessel may not be the culprit vessel for a previous MI.

  7. Have given signed informed consent to participate in this study.

Exclusion Criteria:

  1. Clinically significant heart disease which will require coronary bypass, PCI, cardiac transplantation, surgical repair and/or replacement during the course of the study.
  2. Any elective surgical procedure that would require general anesthesia during the course of the study.
  3. Coronary artery bypass graft (CABG) procedure within the past 90 days.
  4. Previous or current diagnosis of severe heart failure (NYHA Class III-IV) or a documented left ventricular ejection fraction (LVEF) of <25 percent as determined by contrast left ventriculography, radionuclide ventriculography or echocardiography, the absence of an LVEF measurement in a patient without a previous or current diagnosis of heart failure does not prohibit entry into the study.
  5. Patients with evidence of cardiac electrophysiologic instability including a history of uncontrolled ventricular arrhythmias, uncontrolled atrial fibrillation/flutter or uncontrolled supraventricular tachycardias with a ventricular response heart rate of >100 beats per minute at rest within 4 weeks prior to Visit 1.
  6. Evidence of renal impairment as determined by any one of the following:

    • serum creatinine >1.5 mg/dL (>133 micromol/L) by central lab at Visit 1,
    • a calculated creatinine clearance less than 60 ml/min at Visit 1
    • a history of dialysis,
    • a history of nephrotic syndrome.
  7. Have hypertension that is uncontrolled defined as 2 consecutive measurements of sitting blood pressure of systolic >160 mm Hg or diastolic >95 mm Hg at Visit 1.
  8. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive beta-hCG laboratory test (>/= 5 mIU/mL).
  9. Current or recent (within 12 month prior to Visit 1) treatment with immunosuppressants (eg, Cyclosporine).
  10. Use of fibrates any dose or niacin/nicotinic acid 250 mg or more within 90 days prior to Visit 1.
  11. Atorvastatin >40 mg daily at Visit 1.
  12. Rosuvastatin >20 mg daily at Visit 1.
  13. Triglycerides >400 mg/dL at Visit 1.
  14. Any medical or surgical condition which might significantly alter the absorption, distribution, metabolism or excretion of medication including, but not limited to any of the following: cholecystitis, Crohn's disease, ulcerative colitis, or any gastric bypass alteration.
  15. Evidence of hepatic disease as determined by any one of the following: a history of hepatic encephalopathy, history of Hepatitis B, C or E, history of esophageal varices, history of porta-caval shunt. Any one of the following liver enzymes that is >ULN by central lab at Visit 1: ALT, AST, GGT
  16. A total bilirubin that is >ULN by central lab at Visit 1.
  17. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.
  18. History or evidence of drug or alcohol abuse within the last 12 months.
  19. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.
  20. Use of other investigational drugs and devices at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
  21. History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
  22. Any condition that in the opinion of the investigator would confound the evaluation and interpretation of efficacy and/or safety data.
  23. Persons directly involved in the execution of this protocol.

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): NCT01067820


Locations
Hide Hide 58 study locations
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Argentina
La Plata, Buenos Aires, Argentina, 1900
Buenos Aires, Argentina, C1180AAX
Buenos Aires, Argentina, C1428DCO
Corrientes, Argentina, 3400
Córdoba, Argentina, 5000
Córdoba, Argentina, X5000EPU
Córdoba, Argentina, X5003DCE
Córdoba, Argentina, X5006IKK
Córdoba, Argentina, X5016KEH
San Isidro, Argentina, B1642DJN
Belgium
Brussels, Belgium, 1200
Charleroi, Belgium, 6000
Edegem, Belgium, B-2650
Genk, Belgium, 3600
Brazil
Brasilia, Brazil, 70390-700
Cariacica, Brazil, 29156-580
Curitiba, Brazil, 80320-320
Goiania, Brazil, 74223-130
Porto Alegre, Brazil, 90020-090
San Paulo, Brazil, 04012-909
Sao Paulo, Brazil, 05403-000
Uberlândia, Brazil, 38400-368
Hungary
Budapest, Hungary, H-1023
Budapest, Hungary, H-1106
Budapest, Hungary, H-1122
Budapest, Hungary, H-1134
Pécs, Hungary, H-7624
Szeged, Hungary, H-6720
Netherlands
Alkmaar, Netherlands, 1814
Amsterdam, Netherlands, 1091
Eindhoven, Netherlands, 5623
Enschede, Netherlands, 7513
Nijmegen, Netherlands, 6532
Rotterdam, Netherlands, 3079
Zwolle, Netherlands, 8011
Poland
Katowice, Poland, 40-635
Warszawa, Poland, 02-507
Warszawa, Poland, 04-628
Russian Federation
Moscow, Russian Federation, 101990
Moscow, Russian Federation, 117931
Moscow, Russian Federation, 121552
Moscow, Russian Federation, 143420
Orenburg, Russian Federation, 460000
Saint Petersburg, Russian Federation, 191104
St. Petersburg, Russian Federation, 197341
Tomsk, Russian Federation, 634012
Spain
Badalona, Spain, 08916
Barcelona, Spain, 08035
Barcelona, Spain, 08907
Cartagena, Spain, 30203
Galdakao, Spain, 48960
Gijón, Spain, 33203
Madrid, Spain, 28040
Madrid, Spain, 28046
Malaga, Spain, 29010
Santander, Spain, 39008
Santiago de Compostela, Spain, 15706
Vigo, Spain, 36214
Sponsors and Collaborators
Resverlogix Corp
The Cleveland Clinic
Investigators
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Principal Investigator: Stephen Nicholls, MBBS, PhD Intravascular Ultrasound Core Lab, Cleveland Clinic
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Resverlogix Corp
ClinicalTrials.gov Identifier: NCT01067820    
Other Study ID Numbers: RVX222-CS-007
First Posted: February 12, 2010    Key Record Dates
Last Update Posted: June 4, 2013
Last Verified: June 2013
Keywords provided by Resverlogix Corp:
ApolipoproteinA1
HDL-C
Atherosclerosis
Additional relevant MeSH terms:
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Coronary Artery Disease
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases