Carotid Atherosclerosis Regression at Magnetic Resonance Assessment.
Condition: Established Carotid Atherosclerosis
MeSH terms: Carotid Artery Diseases; Atherosclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary objective of this randomized, double blind, placebo controlled pilot study is to
      determine if therapies aimed at lowering LDL cholesterol (HMGCoA reductase inhibitor -
      simvastatin) or increasing HDL cholesterol (Niaspan) will induce regression of carotid
      atherosclerotic plaque in vivo using MRI imaging techniques. MR plaque morphology at baseline
      will be compared to that after 6 and 12 months of therapy and changes in MR characteristics
      will be compared to changes in lipoprotein parameters and urinary isoprostanes. The effect of
      moderate LDL reduction, aggressive LDL reduction and the combination of aggressive LDL
      reduction and HDL elevation on MRI plaque characteristics will be compared by randomly
      assigning subjects (n=69) with carotid disease (>30% stenosis by ultrasound criteria) to one
      of three treatment arms;

        1. Simvastatin 20 mg daily and placebo Niaspan (n=23)

        2. Simvastatin 80 mg daily and placebo Niaspan (n=23)

        3. Simvastatin 20 mg daily and active Niaspan (n=23) Treatment group 2 and 3 will have
           roughly equivalent LDL lowering because of the synergistic LDL lowering effect of the
           combination of simvastatin and Niaspan.
    

Detailed description: 
      FULL PROTOCOL

      1.0 SYNOPSIS The primary objective of this randomized, double blind, placebo controlled pilot
      study is to determine if therapies aimed at lowering LDL cholesterol (HMGCoA reductase
      inhibitor - simvastatin) or increasing HDL cholesterol (Niaspan) will induce regression of
      carotid atherosclerotic plaque in vivo using MRI imaging techniques. MR plaque morphology at
      baseline will be compared to that after 6 and 12 months of therapy and changes in MR
      characteristics will be compared to changes in lipoprotein parameters and urinary
      isoprostanes. The effect of moderate LDL reduction, aggressive LDL reduction and the
      combination of aggressive LDL reduction and HDL elevation on MRI plaque characteristics will
      be compared by randomly assigning subjects (n=69) with carotid disease (>30% stenosis by
      ultrasound criteria) to one of three treatment arms;

        1. Simvastatin 20 mg daily and placebo Niaspan (n=23)

        2. Simvastatin 80 mg daily and placebo Niaspan (n=23)

        3. Simvastatin 20 mg daily and active Niaspan (n=23) Treatment group 2 and 3 will have
           roughly equivalent LDL lowering because of the synergistic LDL lowering effect of the
           combination of simvastatin and Niaspan.

      2.0 BACKGROUND Atherosclerotic carotid disease is the largest single etiological factor known
      to produce focal cerebral ischemia (1). Only a small percentage of patients with asymptomatic
      carotid atherosclerosis develop stroke but the majority of these have have no warning
      symptoms. The degree of internal carotid stenosis at ultrasound angiography, the commonest
      methods of assessing the risk of stroke, are poor predictors of stroke in patients with
      asymptomatic carotid atherosclerosis (2) and clinical risk factors have a high prevalence but
      a low relative risk of stroke in these patients. Most plaque rupture occurs in unstable lipid
      rich plaques with thin fibrous caps weakened by inflammation and apoptosis (3). Thus, the
      morphological characteristics of carotid plaques may provide important information regarding
      ischemic risk of carotid lesions. We, and others, are using high resolution MR imaging (4-6)
      to differentiate carotid plaque elements such as the lipid core, the fibrous cap and
      hemorrhage with the ultimate goal of determining the ischemic potential of carotid
      atherosclerotic plaques.

      Lipid lowering therapy with statins is considered standard treatment for patients with
      atherosclerosis and hypercholesterolemia (7-9). Statin therapy reduces LDL cholesterol
      levels, cardiovascular events and death and retards the progression of atherosclerosis as
      assessed by noninvasive intima-media thickness (IMT) on carotid ultrasound (10). However, the
      optimal degree of LDL cholesterol lowering with statins in patients with atherosclerosis
      remains unclear (7,8) - thus there are a number of ongoing large clinical trials comparing
      the effect of low dose to high doses of statins on cardiovascular effects in patients with
      coronary atherosclerosis (eg "Treatment to New Targets"). Low HDL cholesterol is an
      independent risk factor for the development and progression of atherosclerosis (11). Niacin
      is one of a few effective therapies that significantly elevates HDL levels and was shown to
      reduce cardiovascular events in patients with known coronary atherosclerosis prior to the
      development of statin drugs (12,13). Increased HDL is thought to promote reverse cholesterol
      transport from the peripheral tissues including atherosclerotic plaque (14-16). Presently,
      niacin is not considered standard therapy in patients with known atherosclerosis. Niaspan is
      a new controlled-release form of niacin that is administered once daily, is better tolerated
      than crystalline niacin which is given 3 times a day (17,18). It has been shown to result in
      a greater than 30% increase in HDL cholesterol and preliminary data suggest that it is safe
      and effective and not associated with hepatotoxicity (19). In the proposed study patients
      (n=60) with carotid disease (>30% stenosis by ultrasound criteria) will be randomly assigned
      to one of three treatment arms;

        1. Simvastatin 20 mg daily and placebo Niaspan (n=23)

        2. Simvastatin 80 mg daily and placebo Niaspan (n=23)

        3. Simvastatin 20 mg daily and active Niaspan (n=23) Thus, the effect of Simvastatin 10 mg
           (moderate LDL reduction), Simvastatin 80 mg (aggressive LDL reduction) and the
           combination of Simvastatin and Niaspan (aggressive LDL reduction and HDL elevation) on
           MRI plaque characteristics will be compared.

      3.0 OBJECTIVES

      The primary objective of this randomized, double blind, placebo controlled pilot study is to
      determine if therapies aimed at lowering LDL cholesterol (HMGCoA reductase inhibitors -
      statins) or increasing HDL cholesterol (Niaspan) will induce regression of carotid
      atherosclerotic plaque in vivo using MRI imaging techniques. MR plaque morphology at baseline
      will be compared to that after 6 and 12 months of therapy and changes in MR characteristics
      will be compared to changes in lipoprotein parameters and urinary isoprostanes.

      3.1 Primary End-Point The primary end-point is the change in carotid plaque volume at MRI
      after 12 months of treatment.

      3.2 Secondary End-Points

        1. - change in carotid plaque lipid content at MRI after 12 months

        2. - change in lipid parameters after 12 months

        3. - change in urinary isoprostane excretion after 12 months

      4.0 STUDY DESIGN

      4.1 Description

      This study will be randomized, double-blind and placebo controlled. Sixty patients will be
      randomly assigned to (1) Simvastatin 20 mg and placebo Niaspan, (2) Simvastatin 80 mg and
      placebo Niaspan or (3) Simvastatin 20 mg and active Niaspan. The study will involve 6
      outpatient visits to the General Clinical Research Center (GCRC) at the Hospital of the
      University of Pennsylvania. Each visit will last approximately 2 hours.

      4.2 Number of Subjects

      Sixty nine (69) subjects with known carotid atherosclerosis will be investigated.

      5.0 STUDY POPULATION

      Source of subjects

      Subjects with carotid disease, identified on (1) routine carotid ultrasound examinations at
      the vascular laboratories of the University of Pennsylvania Health System and VA Medical
      Center, and (2) through local advertisement will be invited to participate in the study.
      Subjects will be contacted by letter inviting them to participate in the study. Subjects will
      be screened according to the following inclusion and exclusion criteria;

      Inclusion Criteria Age >18 and <90 years Capacity for giving written informed consent Carotid
      stenosis of >30% by ultrasound criteria LDL cholesterol level of >100mg/dl Systolic BP < 170
      and diastolic BP < 100 under resting conditions Negative pregnancy test if female of
      child-bearing potential

      Exclusion criteria Recent (< 3 months) history of stroke, transient ischemic attack,
      myocardial infarction, unstable angina or critical limb ischemia, Contraindications to MRI
      (claustrophobia, presence of pacemakers, defibrillators, metal foreign bodies), History of
      side effect/adverse reaction on HMGCoA reductase inhibitor, Niaspan or niacin, Poorly
      controlled diabetes (HbA1c >8%), History of myositis, liver disease or abnormal LFTs, Need
      for combination therapy for the control of severe hyperlipidemia, Abnormal LFT (>2 fold upper
      limit normal), Active infection or malignancy.

      6.0 STUDY PROCEDURES The study will involve 6 outpatient visits to the General Clinical
      Research Center (GCRC) at the Hospital of the University of Pennsylvania. Each visit will
      last approximately 2 hours.

      6.1 Pre-treatment Period All subjects will be asked to come to GCRC for a screening visit.
      During this visit, a complete medical history and physical examination will be performed.
      Dosage of all chronic medication will be recorded. Supine resting blood pressure, an
      electrocardiogram and the following fasting routine laboratory studies will be performed;
      Hematology; hemoglobin, hematocrit, MCV, white blood count and platelet count Blood
      chemistries; sodium, potassium, chloride, creatinine, fasting glucose, albumin, alkaline
      phosphatase, total bilirubin, AST, ALT, uric acid total cholesterol, LDL, HDL, triglycerides
      lipoprotein (a) and HbA1c.

      Urinalysis Urinary HCG - for women of child bearing potential. Eligible subjects will undergo
      a full dietary assessment by the GCRC research dietician using a quantitative questionnaire.
      Subjects will be instructed to comply with recommended AHA dietary guidelines so that dietary
      intake of macronutrients including fat and cholesterol will be similar across all subjects.
      Dietary compliance will be monitored at baseline and each study visit by 24-hour recall of
      dietary intake. The Dietary Analysis System (DIETSYS) will be used to analyze the food
      frequency questionnaires and the Food Processor Plus (ver 6.0) will be used to analyze
      dietary recalls.

      6.2 Concurrent Treatment The use of most concurrent medications will not be restricted during
      the study period. Indeed, aspirin use and antihypertensive therapies will be encouraged when
      appropriate. Lipid lowering medications, other than those in the study will be stopped prior
      to randomization. For example all HMGCoA reductase inhibitors will be replaced by simvastatin
      at the time of randomization.

      6.3 Treatment Period Eligible subjects will be asked to collect a 12-hour urine sample prior
      to randomization and bring them to the GCRC on the morning of randomization where they will
      be processed and stored until analysis. Baseline blood samples will be collected for
      hematology, chemistry and lipoprotein analysis as per screening. Subjects will undergo micro
      MRI scans of the carotid arteries in the MRI center adjacent to the GCRC. A subset of
      volunteers (n=10) will be asked to undergo a second baseline MRI scan within a week of the
      first scan in order to determine the reproducibility of the quantitative MRI technique.
      Subjects will then be randomized in a double blind manner to (1) Simvastatin 20 mg and
      placebo Niaspan, (2) Simvastatin 80 mg and placebo Niaspan or (3) Simvastatin 20 mg and
      active Niaspan. Simvastatin tablets will be provided by Merck Pharmaceuticals, the
      manufacturer of Simvastatin. Niaspan tablets (500mg) and matching placebo will be provided by
      KOS, the company that manufactures Niaspan. Niaspan will be titrated according to clinical
      guidelines - 500 mg at bedtime for 1 month, 1000 mg at bedtime for the next month and finally
      2000 mg at bedtime for the rest of the study. At the randomization visit, these specific
      instructions for titration of Niaspan or placebo (given in matching tablets in an identical
      way) will be discussed and given to each subject with a one-month supply of study drug.

      Both Niaspan (KOS Pharmaceuticals) and simvastatin (Zocor; Merck Pharmaceuticals) are
      commercially available drugs that are FDA approved for management of hyperlipidemia at the
      doses, formulation and route of administration proposed in this study.

      Return visits will be scheduled for 1, 3, 6 and 12 months. At each of these visits history,
      physical exam and blood testing (hematology, chemistry, fasting lipoproteins) will be
      undertaken. In addition, urine collections and MRI studies will be performed at 6 and 12
      months. Known adverse effects, such as flushing and muscle cramps will be screened for at
      each visit. Subjects will be discontinued from the study for the following reasons;

        1. intolerable side effects from the study medications

        2. increase in either ALT or AST greater than 3 times upper limit of normal

        3. HbA1c>9%

        4. uric acid >11.0

        5. pregnancy

      Eligible subjects will be asked to increase study medication to 2000mg daily at bedtime after
      the second month. Every attempt will be made to titrate the Niaspan/placebo to 2000mg per
      day, but if this is not possible the subject will be maintained on the maximal achievable
      dose. The duration of the study is 12 months. All assessments will be made by personnel
      blinded to the study treatment.

      6.4 Duration of the Study The duration of the entire study will be approximately 18 months.
      Actual study drug treatment will be of 12 months duration. Each subject will undergo
      screening approximately 2 weeks prior to randomization and it is anticipated that subjects
      will be enrolled over a 6 month period.

      6.5 Premature Withdrawal from the Study

      A volunteer may be withdrawn from the trial for the following reasons:

        -  Any adverse event thought to warrant withdrawal by the investigator,

        -  Poor compliance thought to warrant withdrawal by the investigator,

        -  Volunteer's desire to withdraw from the study at any time,

        -  Protocol or entry criteria violation,

        -  Pregnancy.

      The reasons for withdrawal and the final outcome in cases of adverse events will be
      documented on the Case Report Form. Subjects who do not complete the study will be replaced.

      7.0 EFFICACY ASSESSMENT

      7.0 Variables to be measured for Efficacy Assessment Magnetic Resonance Imaging of Carotid
      Atherosclerotic Plaques: A variety of MRI techniques have been optimized to permit sufficient
      resolution to determine size and composition of atherosclerotic plaque. These include
      "black-blood" imaging techniques, fast spin echo sequences, and fat suppression techniques in
      addition to customized coils (4-6). Customized surface coils will be constructed to further
      improve the signal-to-noise ratio. While the coils and some of the sequences are not FDA
      approved as they are custom built, they all fall under the category of "non-significant risk
      devices". These techniques have already been established for this purpose at the MRI center
      at the Hospital of the University of Pennsylvania. The imaging protocol consists of a
      combination of black blood (fast spin echo and double inversion recovery fast spin echo
      sequences) and bright blood imaging (time-of-flight MRA sequence) to achieve optimal contrast
      between the arterial lumen and the vessel wall. Specifically, the following sequences are
      obtained: (1) 3D time of flight (TOF) MRA of the carotid bifurcation; (2) axial T1-weighted
      fast spin echo; (3) axial proton density-weighted weighted double inversion recovery fast
      spin echo (DIR-FSE) through plaque; and (4) axial T2-weighted weighted DIR-FSE through
      plaque. Total plaque volume will be quantified as follows;

      Plaque volume = (computer assisted calculation of region of interest-ROI) x (slice thickness)
      x (no. of slices).

      Plaque composition will be estimated using established imaging criteria for the 4 image
      contrast weightings (Table 1).

      Table 1 Criteria used for identification of plaque constituents. TOF T1-W PD-W T2-W
      Calcification Low Low Low Low Hemorrhage High High/Moderate Variable Variable Lipid core
      Moderate High High Variable Fibrous cap Moderate/Low Moderate High Variable Note: Intensity
      descriptors are relative to intensity of sternocleidomastoid muscle.

      Lipoprotein Determination: Total cholesterol, LDL cholesterol, HDL cholesterol, lipoprotein
      (a) and triglyceride levels will be determined by standardized techniques in the routine
      chemistry laboratory of the Hospital of the University of Pennsylvania.

      Urinary Isoprostanes: Urinary isoprostanes will be measured by mass spectrometry / gas
      chromatography (GC / MS) as previously described by the PI (20). Following the addition of a
      deuterated isoprostane internal standard, urine samples are extracted from the aqueous matrix
      by solid phase extraction techniques, purified by thin layer chromatography, derivatized, and
      analyzed by GC / MS in the negative ion chemical ionization (NICI) mode. Quantification is
      accomplished by taking the ratio of the area under the peak of the ion representing the
      endogenous compound to that of the internal standard.All subjects who complete the study will
      be considered evaluable for efficacy assessment.

      7.2 Criteria for Evaluability of Efficacy Assessment

      All subjects who complete the study will be considered evaluable for efficacy assessment.

      8.0 SAFETY ASSESSMENT

      8.1 Variables to be Measured for Safety Assessment

      Safety measures to be monitored include

        1. symptoms (flushing, abdominal pain, tiredness)

        2. transaminases

        3. HbA1c

        4. uric acid

      8.2 Criteria for Evaluability of Safety Assessment

      All subjects entered into the trial will be considered evaluable for safety assessment.

      9.0 STATISTICAL CONSIDERATIONS

      There is currently no data available on the effect of therapies on carotid atherosclerotic
      plaque morphology using MRI on which to base sample size estimations. Therefore, sample sizes
      are based on the desire to acquire pilot data to allow the determination of the actual
      numbers required for a study examining both MR characteristics and clinical endpoints. A
      sample size of 69 (23 subjects per arm) will provide 80% power to detect the hypothesized
      difference (15%) in the primary endpoint (plaque volume) between 2 different treatment arms
      at an alpha of 0.05. The number of subjects needed for future full-scale clinical studies
      will be dependent on the coefficient of variation of repeated baseline quantitative MRI scans
      and the change in plaque volume (primary end-point) following an intervention. These
      parameters will be defined by the proposed pilot study.

      10.0 DATA COLLECTION, MONITORING AND AE REPORTING

      10.1 Case Report Forms

      Case Report Forms (CRFs) will be provided for each subject. Subjects must not be identified
      by name on any study documents. Subjects will be identified by the Patient Identification
      Number (PIN) and Study Identification Number (SID). All data on the CRF will be legibly
      recorded in black ink or typed. Corrections will be made by striking the incorrect entry with
      a single line through it and then adding the correct information adjacent to it. The
      corrections will be initialed and dated by the investigator or designated qualified
      individual. Any requested information that is not obtained as specified in the protocol will
      be indicated on the CRFs as "not done" (ND) or "not applicable" (NA).

      10.2 Data Management

      The CRF design and data management will be performed by the PI and research assistants.

      10.3 Monitoring

      The PI will review the research records for accuracy, completeness and legibility. The
      investigator or designated qualified individual will make study documents (eg consent forms,
      drug distribution forms, case report forms) and pertinent hospital or clinic records
      available for inspection by the Food and Drug Administration (FDA) for conformation of the
      data.

      10.4 Adverse Experience (AE) Reporting

      Adverse Experiences (AEs) will be monitored throughout the study and such events will be
      recorded on the Adverse Experience Case Report Forms. An AE is defined as any unfavorable and
      unintended change in the structure, function or chemistry of the body temporally associated
      with the use of the study medication, whether or not considered related to the use of the
      product. The AEs will be graded on a three-point scale (mild, moderate severe) and a drug
      relationship assigned.

      Any serious or unexpected adverse events will be reported within 24 hours to the FDA and the
      IRB of the University of Pennsylvania. Adverse events are defined as serious when they are
      fatal, life-threatening or result in in-patient hospitalization or prolongation of
      hospitalization. In addition the occurrence of malignancy is always considered serious
      adverse advents. Adverse events are considered unexpected if their occurrence, or severity or
      frequency have not been previously reported in concomitance with Niaspan or HMGCoA reductase
      inhibitor therapy.

      11.0 ETHICAL CONSIDERATIONS

      11.1 Institutional Review Board (IRB)

      The study protocol will be reviewed by the committee on Studies involving Human Beings at the
      University of Pennsylvania. A copy of the letter of approval and correspondence with the IRB
      will be retained by the investigators.

      11.2 Informed Consent

      Written informed consent will be obtained from every volunteer participating in the study
      after adequate explanation of the object of the study and possibly adverse effects of the
      drug treatment.

      11.3 Subject Confidentiality

      The medical information gathered during this study will be treated confidentially except as
      may be required by law. Regulatory authorities, including the US Food and Drug
      Administration, might review the medical records to verify the accuracy of the information
      collected. Subjects will not be identified by name on any study documents and, if the results
      are published the subjects' identity will not be disclosed.

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Intervention name(s): Niacin/simvastatin compared to simvastatin alone at 2 doses
Intervention type(s): Drug
Intervention MeSH terms: Niacin; Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: atherosclerosis; HDL cholesterol; niacin; MR imaging