Study of 3,5-Diiodothyropropionic Acid (DITPA) in Hypercholesterolemic Patients
Study of 3,5-Diiodothyropropionic Acid (DITPA) in Hypercholesterolemic Patients
The natural thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are known to have a
 cholesterol-lowering effect. Their pharmacologic use for this purpose is limited, however, by
 their actions on other organs, including the heart, bone, and brain, where there can be side
 effects of excessive thyroid hormone action. 3,5-diiodothyropropionic acid (DITPA) is a
 thyroid hormone analog with relative selectivity for a form of the thyroid hormone receptor
 expressed in the liver, where it regulates several aspects of lipid metabolism, including the
 clearance of low-density lipoprotein (LDL) cholesterol.

 This study is designed to determine whether DITPA is safe and effective in achieving LDL
 cholesterol levels that are consistent with the National Cholesterol Education Program Adult
 Treatment Panel III (NCEP ATP III) guidelines in patients who have not achieved those levels
 on conventional therapy, due to drug-resistant disease, drug intolerance, or both.

 This is a single-center, randomized, double-blind, placebo-controlled study. Following a
 4-week Pre-Randomization Phase with dietary counseling and a 2-week placebo run-in, eligible
 patients will be randomized (1:1:1) to receive DITPA (90 mg/day, 180 mg/day), or placebo for
 a total treatment duration of 12 weeks.

 Sixty (60) patients will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio (i.e., 20
 patients per treatment group):

 -  DITPA at 90 mg/day (45 mg twice a day [BID] taken orally)

 -  DITPA at 180 mg/day (90 mg BID taken orally)

 -  Placebo (BID taken orally)

 Those patients randomized to receive DITPA at 90 mg/day will receive 45 mg/day for the first
 2 weeks, followed by 90 mg/day for 10 weeks.

 Those patients randomized to receive DITPA at 180 mg/day will receive 45 mg/day for the first
 2 weeks, followed by 90 mg/day for the next 2 weeks, and then 180 mg/day for 8 weeks.
INTRODUCTION

 BACKGROUND: In recent years, the need to achieve increasingly ambitious therapeutic goals for
 dyslipidemias has prompted the search for more potent pharmacological agents to lower
 circulating atherogenic lipoprotein concentrations and enhance reverse cholesterol transport
 (RCT). While mounting evidence supports the use of 3-hydroxy-3-methylglutaryl coenzyme
 reductase inhibitors (or statins) as the main stay of therapy for patients requiring lipid
 modification therapy, many patients remain under-treated or do not achieve the National
 Cholesterol Education Program (NCEP) recommended goals.1-5 Recognizing new and emerging data,
 NCEP III recently updated its guidelines to recognize the potential of a more aggressive low
 density lipoprotein (LDL) goal of <70 mg/dl in patients at high risk of cardiovascular
 events.3 The Treating to New Targets (TNT) study showed that even in patients with stable
 coronary artery disease, a goal that is lower than currently recommended, <80 mg/dl, may be
 desirable in further reducing and/or preventing recurrent cardiovascular events.6 More than
 40% of all Americans have LDL levels of 130 mg/dl or higher, and 13 million Americans have
 coronary artery disease that may benefit from lipid modification therapy. In these
 individuals, to achieve the optimal LDL goal and to treat other associated lipid
 abnormalities, including low HDL cholesterol and/or high triglycerides, many patients will
 likely require combination therapy.3, 7-13 Among the novel therapeutic agents investigated
 have been selective thyroid hormone analogues. Such agents hold the promise of harnessing the
 cholesterol-lowering properties of the naturally occurring thyroid hormones, triiodothyronine
 (T3) and thyroxine (T4), but with greater receptor isoform and tissue specificity that should
 result in an improved safety profile.14, 15 Unlike statins, thyroid hormones and their
 analogues, in addition to cholesterol and LDL-lowering effects, may favorably lower
 lipoprotein (a) (Lp(a)) and triglyceride levels.15-22 Also, because of potential thyroid
 hormone-mediated genomic and non-genomic effects on the heart, certain populations, such as
 those with congestive heart failure, may derive dual benefits from use of such thyromimetic
 treatment.15, 22, 23 1.1.1 Effects of Thyroid Hormone on Lipid Metabolism Dyslipidemia has
 long been associated with disorders of thyroid metabolism (i.e., hypothyroidism) and to be
 potentially reversible by thyroid hormone therapy.17, 18, 21 Early autopsy series
 demonstrated more severe atherosclerosis in individuals with premorbid hypothyroidism.24, 25
 In studies of how thyroid hormone status affected radiolabeled lipoprotein kinetics, LDL was
 found to be cleared less rapidly in hypothyroid animals and man.26 Subsequently, hepatic LDL
 receptor number27 and mRNA expression28 were shown to be lower in hypothyroid animals. More
 recently, characterization of the LDL receptor gene promoter has revealed the presence of
 functionally important T3 regulatory elements.29 In addition to lowering total and LDL
 cholesterol concentrations in treated hypothyroid patients, thyroid hormone therapy has been
 shown in some studies to have a favorable impact on particularly atherogenic lipoproteins,
 including Lp(a)30 and small dense and oxidizable LDL subfractions.31, 32 Finally, thyroid
 hormone replacement therapy has been shown to decrease apoB100 lipoprotein synthesis with a
 resulting decrease in Very Low Density Lipoprotein (VLDL) production and hepatic triglyceride
 production.33 There is now also considerable evidence that thyroid hormone receptor agonists
 can directly or indirectly affect reverse cholesterol transport, the process by which
 cholesterol is transported from peripheral cells, including cholesterol-laden endothelial
 cells in the initial stage of atherosclerosis, to the liver for conversion to bile acids.
 First, thyroid hormone affects the activity of apoA 1 lipoprotein,34 which plays several
 critical roles in RCT-generating HDL that transports cholesterol from peripheral tissues to
 the liver, as both the principal protein constituent of HDL and an activator of
 lecithin-cholesterol acyltransferase (LCAT), which esterifies cholesterol on the surface of
 pre-β-HDL. ApoA-I also stabilizes and increases the level of ATP-binding cassette A1 protein
 (ABCA1), which, in turn, promotes efflux of cholesterol and phospholipids to nascent
 HDL-particles. Thyroid hormone increases apoA-I gene expression in liver and intestine, in
 part through a 5' flanking thyroid hormone response element.35, 36 Thyroid hormone has also
 recently been shown to increased the scavenger class B type I receptor (SR-BI), another
 regulator of serum HDL concentrations and cholesterol flux, in livers of mice treated with
 either T3 or GC-1 (a thyroid hormone receptor modulator).37 Finally, thyroid hormones are
 also known to increase activity of cholesterol 7α-hydroxylase (CYP-7A1)38 which catalyzes the
 rate-limiting step in bile acid synthesis; in contrast, HMG-CoA reductase inhibitors have the
 opposite effect. This thyroid hormone-induced increase in CYP-7A1 would be expected to
 increase bile acid and cholesterol excretion, as has been observed in hyperthyroidism.39
 1.1.2 Previous Clinical Research Previous studies have investigated the therapeutic potential
 of thyromimetic compounds in lipid modification and heart failure.14,15,40 Early clinical
 investigation focused on dextrothyroxine (D-T4), a D-isomer of thyroxine, which was thought
 to have similar actions, but produce less tachycardia and myocardial oxygen consumption.40,
 41 Although DT4 was commonly used as a cholesterol lowering drug in the 1970s,42 it is no
 longer used in clinical practice. The therapeutic effects of DT4 were evaluated in the
 Coronary Drug Project (CDP).

 The Coronary Drug Project was initiated in 1965, primarily to answer the prevailing question
 about the safety and efficacy of long term use of various cholesterol lowering agents in
 patients with coronary artery disease. The Coronary Drug Project was a randomized,
 double-blind, placebo-controlled study, conducted between 1966 and 1975. It was designed to
 evaluate the efficacy and safety of five lipid-modifying drugs in 8,341 men, with a history
 of prior myocardial infarction (MI). Niacin, clofibrate, dextrothyroxine, and two estrogen
 regimens were evaluated in the study along with a placebo arm.43, 44 DT4 was administered at
 6.0 mg /day. The primary endpoint was overall mortality at 5 years. After a mean follow-up of
 36 months, because of a nonsignificant trend toward higher mortality in the DT4 arm compared
 with placebo, the DT4 arm was discontinued.

 As acknowledged by the original investigators, the observed DT4-placebo difference in overall
 mortality is not statistically significant as judged by the statistical methods utilized in
 this study.44 Nevertheless, given the mortality trend and the low probability of eventual
 benefits, a decision was made to discontinue the DT4 arm. In discontinuing the DT4 arm, the
 study leadership recognized that the findings of the CDP left open the possibility that
 dextrothyroxine may be efficacious for a limited group of carefully selected myocardial
 infarction (MI) patients and for persons free of clinical CHD. 44 The net effect of DT4 on
 serum lipids (the observed fall corrected for the concomitant rise for the placebo group) was
 a sustained significant fall from baseline levels. The decrease was approximately 12% in
 serum cholesterol levels and 15-20% in fasting serum triglyceride levels.44 Following the
 study, it was revealed that the DT4 dispensed in the study contained less than 0.5% of
 levothyroxine (approximately 30 µg of levothyroxine).44 Interestingly, it was later found
 that contamination of levothyroxine commercial preparations varied from lot to lot (from 0.5%
 to 2.3%).45 Also, this "DT4" formulation had other significant thyromimetic effects, leading
 to TSH suppression that may have become clinically relevant with prolonged use.47 Suboptimal
 dosing and thyrotoxic effects due to drug contamination may explain why more than 40% of the
 DT4 patients required a dose reduction.44 1.1.3 DITPA DITPA (3,5-diiodothyropropionic acid)
 is an analogue of naturally occurring thyroid hormone (T3) that has been specifically
 designed to improve cardiac performance with a lower potential for tachycardia.22, 40, 46
 DITPA binds to the same thyroid hormone receptors α and β as T3 but with less affinity.41 In
 pre-clinical animal post-infarction models, DITPA improved calcium handling, promoted
 angiogenesis, and attenuated abnormal left ventricular remodeling.47-53 In a rat model of
 CHF, DITPA demonstrated increased cardiac output with increases in left ventricular dp/dt,
 comparable to effects seen with T4, but with significantly less tachycardia. In addition,
 there were increases in α-myosin heavy chain (MHC) RNA gene expression induced by DITPA
 treatment.41 When evaluated in combination with captopril, DITPA improved both cardiac output
 and dp/dt as well as increased the rate of LV relaxation when compared with captopril
 alone.54 In a rabbit post-infarction model, DITPA decreased left ventricular end diastolic
 pressure and increased positive and negative dp/dt without changes in heart rate or left
 ventricular systolic pressure.43 In the same model, use of DITPA prevented abnormal SERCA
 transport and abnormal contractile function associated with myocardial infarction.42, 44
 Recently DITPA was also noted to improve endothelial function following myocardial
 infarction, an action mediated through nitric oxide.55 The objective of the present study is
 to evaluate the feasibility of DITPA, a thyroid hormone analogue, as a potential lipid
 modification agent.

 KNOWN AND POTENTIAL TOXICITIES: Since DITPA is a thyroid hormone analogue with thyromimetic
 actions, safety and side effect profiles may be similar to those observed with thyroid
 hormones T3 and T4 preparations (e.g., liothyronine and levothyroxine). Although excess
 thyromimetic action is a theoretical side effect, it is also possible that tissue-specific
 hypothyroidism might result if the drug fails to have sufficient thyromimetic activity in a
 particular tissue. Due to pituitary effects of DITPA, a secondary lowering of TSH may result,
 which in turn may lead to decreased endogenous production of T4. The potential effects of
 such theoretical biochemical changes are unknown. Thus, DITPA safety will be diligently
 monitored throughout the study through multiple examinations, symptom scales, and laboratory
 evaluations.

 Based on the known effects of thyrotoxicosis and hypothyroidism, and the side effects of T3
 and T4 preparations, potential side effects of DITPA may include:

 1. Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood
 pressure, heart failure, angina, myocardial infarction, cardiac arrest

 2. Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability,
 emotional lability, insomnia

 3. Dermatologic: hair loss, warm moist or dry skin, flushing

 4. Endocrine: decreased bone mineral density, gynecomastia

 5. Gastrointestinal: diarrhea or constipation, vomiting, abdominal cramps, elevations in
 liver function tests

 6. General symptoms: fatigue, increased appetite, excessive sweating

 7. Musculoskeletal: tremors, muscle weakness, proximal myopathy

 8. Respiratory: dyspnea

 9. Reproductive: menstrual irregularities, impaired fertility

 10. Metabolic: weight loss or gain, heat or cold temperature intolerance, fever Please
 consult the most recent DITPA Investigator's Brochure (IB) including amendments for
 additional information.

 In addition, many drugs are known to affect thyroid hormone pharmacokinetics and metabolism
 by altering absorption, synthesis, secretion, protein binding, and/or target tissue response,
 and may also alter the therapeutic response to thyroid hormone preparations such as
 levothyroxine. In addition, thyroid hormones and thyroid status may have varied effects on
 the pharmacokinetics and actions of other drugs. A list of drug-thyroidal axis interactions
 is provided in the prescribing information for marketed agents such as Synthroid®
 (levothyroxine sodium tablets, USP), Abbott Laboratories and Cytomel® (liothyronine sodium
 tablets), King Pharmaceuticals, Inc.

 STUDY DESCRIPTION

 STUDY OBJECTIVES:

 Primary Objective

 -  To evaluate DITPA as a lipid modifying agent in combination with standard therapy in
 patients with LDL-C levels greater than the NCEP ATP III goals as determined by
 patient's risk category, in order to achieve NCEP III LDL-C goals (see Appendix C).

 Secondary Objectives

 -  To evaluate the effect of DITPA on other lipid targets: triglyceride, total cholesterol
 , ratio of total cholesterol to HDL, ratio of LDL to HDL, HDL cholesterol, lipoprotein a
 (Lp (a)), apolipoprotein A-I, apolipoprotein B100, and LDL subfractions

 -  To evaluate the effect of DITPA on weight and waist circumference

 -  To evaluate the effect of DITPA on high sensitive C-reactive protein (hs CRP)

 -  To evaluate the safety of DITPA in this patient population

 STUDY DESIGN: This is a single-center, randomized, double-blind, placebo-controlled study to
 evaluate hyperlipidemic patients on standard lipid-lowering therapy with LDL-C levels
 exceeding NCEP ATP III goals. Following a 4-week Pre-Randomization Phase with dietary
 counseling and a 2-week placebo run-in, eligible patients will be randomized (1:1:1) to
 receive DITPA (90 mg/day, 180 mg/day), or Placebo for a total treatment duration of 12 weeks.

 Sixty 60 patients will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio (i.e., 20
 patients per treatment group):

 -  DITPA at 90 mg/day (45 mg BID taken orally)

 -  DITPA at 180 mg/day (90 mg BID taken orally)

 -  Placebo (BID taken orally)

 Those patients randomized to receive DITPA at 90 mg/day will receive 45 mg/day for the first
 2 weeks, followed by 90 mg/day for 10 weeks.

 Those patients randomized to receive DITPA at 180 mg/day will receive 45 mg/day for the first
 2 weeks, followed by 90 mg/day for next 2 weeks, and then 180 mg/day for 8 weeks.

 Q1, Q2 = first and second qualifying LDL cholesterol values using Friedewald's calculation

 STUDY DURATION AND NUMBER OF VISITS: The study will consist of a Screening Phase with ATP III
 diet counseling, a Pre-Randomization Phase that will consist of dietary counseling plus a
 2-week Placebo Run-In Period, and a 12-week Treatment Phase. Patients will be seen 28 days
 after the End of Treatment Visit. The total duration on study will be approximately 20 weeks.

 Patients will be seen for approximately 9 visits: Screening visit, 2 Pre-Randomization visits
 (Q1 and Q2), a Baseline/Week 0 visit, Week 2, 4, 8, 12/ End of Treatment visits, and a Week
 16/Follow-up visit.

 STUDY DRUG

 STUDY DRUG TREATMENTS TO BE ADMINISTERED: DITPA Capsules 3,5-Diiodothyropropionic acid, or
 DITPA, is the active pharmaceutical ingredient (API). The chemical structure of DITPA is
 shown below: Molecular Formula: C15H12I2O4 Molecular Weight: 510.1 Chemical Name:
 3,5-diiodothyropropionic acid

 DOSING INFORMATION: Patients should be instructed to take 1 capsule in the morning 30 minutes
 before breakfast, and 1 capsule in the evening 30 minutes before the evening meal. The 2
 doses should be taken approximately 10-12 hours apart. Capsules should be taken by mouth with
 a full glass of water. Patients should be instructed not to crush, break, or chew the
 capsules, and to swallow the capsules whole.

 BLINDING: Treatment assignments and administration will be double-blinded. All patients will
 receive medication cards containing study drug capsules (active and/or placebo). The 45 mg,
 90 mg, and placebo capsules will appear identical and the dose will be unidentifiable.

 STUDY SUBJECTS

 STUDY POPULATION: The study population consists of patients who have LDL-C levels greater
 than NCEP III ATP goals as determined by patient's risk category despite standard lipid
 modification therapy.

 CRITERIA TO ENTER STUDY (PRE-RANDOMIZATION PHASE)

 Pre-Randomization Criteria:

 Patients are eligible for study entry based on the following criteria:

 1. Male or female greater than or equal to 18 years of age

 2. Females must not be pregnant or lactating. Females of childbearing potential and males
 must use a reliable means of contraception

 3. LDL-C level greater than the NCEP goals as determined by patients' risk category
 according to NCEP ATP III criteria

 4. Risk category for coronary heart disease and coronary heart disease equivalent with LDL
 goal of <100 mg/dL

 5. Baseline lipid criteria: LDL-C = 100 to160 mg/dL and Triglyceride level = 100 to 500
 mg/dL

 6. Normal Thyroid Function Tests (total T3, total T4, and TSH)

 7. Hemoglobin A1C <8.5 % on a stable oral hypoglycemic or insulin regimen

 8. On stable lipid modification pharmacotherapy (including a statin) for at least 2 weeks
 prior to study entry. Patients must be on at least half maximal doses of statins (as
 assessed by the Investigator), or be intolerant to statins such that the doses are not
 achievable.

 9. Able to give informed consent

 Pre-randomization Exclusion Criteria:

 Patients will not be eligible for the study based on the following criteria:

 1. History of thyroid disorders of any form within 24 weeks prior to study entry

 2. Active liver disease and/or liver transaminases greater than 1.5 X upper limit of normal

 3. Active myocarditis, hypertrophic cardiomyopathy, uncorrected primary valvular disease,
 restrictive cardiomyopathy, uncorrected congenital heart disease, or constrictive
 pericarditis

 4. Myocardial infarction, unstable ischemic heart disease, stroke, or coronary
 revascularization procedure within 24 weeks prior to study entry

 5. Moderate or severe symptomatic congestive heart failure (New York Heart Association
 class III and IV)

 6. Drug or alcohol dependence, or other conditions which may affect study compliance

 7. Renal insufficiency (serum creatinine > 2 mg/dL)

 8. Subjects taking other hormonal therapies (other than oral contraceptive agents and
 postmenopausal hormone replacement therapy) e.g., glucocorticoids, androgens, or growth
 hormones

 9. Use of thyroid supplements (levothyroxine, liothyronine, etc.) or any preparation
 containing thyromimetic agents within 24 weeks prior to study entry

 10. History of coagulopathy or use of anticoagulants such as warfarin

 11. Unstable endocrine/metabolic syndrome that may affect lipid metabolism

 12. History of atrial or ventricular arrhythmia

 13. Diagnosis of other non-cardiac underlying medical conditions expected to impact their
 mortality within 24 weeks after randomization

 CRITERIA FOR RANDOMIZATION

 Randomization Inclusion Criteria:

 Patients are eligible for randomization based on the following criteria:

 1. LDL-C level greater than the NCEP goals as determined by patients' risk category
 according to NCEP ATP III criteria

 2. Risk category for coronary heart disease and coronary heart disease equivalent with LDL
 goal of <100 mg/dL

 3. Baseline lipid criteria: LDL-C = 100 to160 mg/dL (as calculated from Q1 and Q2 lipid
 results) and Triglyceride level = 100 to 500 mg/dL

 4. If on anti-hypertensive therapy, therapy must be stable for at least 4 weeks prior to
 randomization

 5. Stable lipid modification pharmacotherapy for at least 6 weeks prior to randomization

 6. Compliance with medication dosing instructions during the single-blind placebo run -in
 period is 80% to 120% as measured by pill counting.

 Randomization Exclusion Criteria:

 Patients will not be eligible for randomization based on the following criteria:

 1. Significant changes in clinical status from the Screening Visit which would preclude the
 patient from being an appropriate candidate.

 STUDY PROCEDURES: Refer to Appendix A: Schedule of Events for the Sequence and Timing of
 Study Procedures. While every effort must be made to adhere to the schedule, there will
 be a ± 5 day window for each study visit. All visits are in reference to the date of
 randomization.

 SCREENING (VISIT 1):

 A signed informed consent must be obtained prior to any study-specific procedures. The
 following procedures are to be completed at the Screening Visit (4 to 8 weeks prior to
 randomization):

 -  Review list of inclusion/exclusion pre-randomization criteria

 -  Collect laboratory samples:

 -  Hematology/chemistry

 -  Urine sample

 -  Pregnancy test

 -  Thyroid function tests

 -  Fasting lipid panel

 -  Future tests may include lipoprotein (a), NMR lipoprotein subfraction
 analysis, homocysteine, inflammatory markers (PAI-1, selectins, interleukins,
 myeloperoxidase, matrix metalloproteinases) and markers for metabolism (leptin
 and adiponectin)

 -  Dietary counseling (ATP III)

 PRE-RANDOMIZATION VISIT (Q1 - VISIT 2):

 -  Collect laboratory samples: Fasting lipid panel (first qualifying LDL-C (Q1))

 -  Dietary counseling (ATP III)

 PLACEBO RUN-IN VISIT (Q2 - VISIT 3):

 -  Collect laboratory samples:

 -  Fasting lipid panel (second qualifying LDL-C (Q2))

 -  PT/INR

 -  Future tests may include lipoprotein (a), NMR lipoprotein subfraction
 analysis, homocysteine, inflammatory markers (PAI-1, selectins, interleukins,
 myeloperoxidase, matrix metalloproteinases) and markers for metabolism (leptin
 and adiponectin)

 -  Assess patient for qualifying mean calculated LDL-C

 -  Dietary counseling (ATP III)

 -  Dispense placebo 2-week medication card

 BASELINE (VISIT 4):

 Once the patient is deemed eligible, the following baseline procedures should be
 completed within 7 days prior to randomization:

 -  Assess patient drug compliance (placebo run-in)

 -  Review list of inclusion/exclusion randomization criteria

 -  Obtain a patient randomization number and kit number (within 2 days prior to study
 drug administration)

 -  Review medical and medication history

 -  Physical examination, vital signs, weight, height, eye examination, waist
 measurement

 -  DEXA scan for body fat composition and bone mineral density

 -  Thyroid symptom assessments: Hyperthyroid Symptom Scale, Modified Billewicz Index
 for Hypothyroidism, and Hypothyroid Symptom Scale

 -  Echocardiogram

 -  Electrocardiogram (ECG)

 -  Collect laboratory samples:

 -  Hematology/chemistry

 -  Urinalysis

 -  hsCRP

 -  Serum bone markers (osteocalcin, N-telopeptides)

 -  Pregnancy test

 -  Thyroid function tests

 -  Fasting lipid panel

 -  Future tests may include lipoprotein (a), NMR lipoprotein subfraction
 analysis, homocysteine, inflammatory markers (PAI-1, selectins, interleukins,
 myeloperoxidase, matrix metalloproteinases) and markers for metabolism (leptin
 and adiponectin)

 -  PT/INR

 -  DITPA concentration

 -  Pre-randomization adverse events and concomitant medications

 TREATMENT PERIOD (VISIT 5):

 -  Obtain a new kit number

 -  Physical examination, vital signs, weight, eye examination, waist measurements

 -  Thyroid symptom assessments: Hyperthyroid Symptom Scale, Modified Billewicz Index
 for Hypothyroidism, and Hypothyroid Symptom Scale

 -  Adverse events and concomitant medications

 -  Collect laboratory samples:

 -  Thyroid function tests

 -  Fasting lipid panel

 -  Future tests may include lipoprotein (a), NMR lipoprotein subfraction
 analysis, homocysteine, inflammatory markers (PAI-1, selectins, interleukins,
 myeloperoxidase, matrix metalloproteinases) and markers for metabolism (leptin
 and adiponectin)

 -  DITPA concentration

 -  Dispense study drug and assess study drug compliance

 TREATMENT PERIOD (VISIT 6):

 -  Obtain a new kit number

 -  Physical examination, vital signs, weight, eye examination, waist measurement

 -  Thyroid symptom assessments: Hyperthyroid Symptom Scale, Modified Billewicz Index
 for Hypothyroidism, and Hypothyroid Symptom Scale

 -  ECG

 -  Adverse events and concomitant medications

 -  Collect laboratory samples:

 -  Hematology/chemistry

 -  Urinalysis

 -  Pregnancy test

 -  Thyroid function tests

 -  Fasting lipid panel

 -  Future tests may include lipoprotein (a), NMR lipoprotein subfraction
 analysis, homocysteine, inflammatory markers (PAI-1, selectins, interleukins,
 myeloperoxidase, matrix metalloproteinases) and markers for metabolism (leptin
 and adiponectin)

 -  PT/INR

 -  DITPA concentration

 -  Dispense study drug and assess study drug compliance

 TREATMENT PERIOD (VISIT 7):

 -  Obtain a new kit number

 -  Physical examination, vital signs, weight, eye examination, waist measurement

 -  Adverse events and concomitant medications

 -  Collect laboratory samples:

 * Hematology/chemistry

 * Urinalysis

 -  Pregnancy test

 -  Fasting lipid profile

 -  DITPA concentration

 -  Dispense study drug and assess study drug compliance

 END OF TREATMENT VISIT (VISIT 8): Study patients who have completed 12 weeks of
 treatment, or who have discontinued early (prior to Week 12) will be evaluated at the
 End of Treatment visit. If evaluations were performed within 1 week of discontinuation,
 they do not need to be repeated, unless follow-up for safety concerns is needed.

 The following Week 12/Visit 8 study procedures should be completed:

 -  Physical examination, vital signs, weight, eye examination, waist measurement

 -  DEXA scan for body fat composition and bone mineral density

 -  Thyroid symptom assessments: Hyperthyroid Symptom Scale, Modified Billewicz Index
 for Hypothyroidism, and Hypothyroid Symptom Scale

 -  Echocardiogram

 -  ECG

 -  Adverse events and concomitant medications

 -  Collect laboratory samples:

 * Hematology/chemistry

 * Urinalysis

 * HsCRP

 * Serum bone markers

 * Pregnancy test

 * Thyroid function tests

 * Fasting lipid panel

 * Future tests may include lipoprotein (a), NMR lipoprotein subfraction analysis,
 homocysteine, inflammatory markers (PAI-1, selectins, interleukins,
 myeloperoxidase, matrix metalloproteinases) and markers for metabolism (leptin and
 adiponectin)

 * PT/INR

 -  Study drug compliance

 FOLLOW-UP VISIT (VISIT 9):

 Study patients will be seen 28 days after the End of Treatment visit. The following
 procedures should be completed during this visit:

 - Physical examination, vital signs, weight, eye examination, waist measurement

 - Assess adverse events and concomitant medications

 - Collect laboratory samples:

 * Hematology/chemistry

 * Urinalysis

 -  Pregnancy test

 -  Thyroid function tests

 -  Fasting lipid profile

 UNSCHEDULED VISITS: Study patients should be evaluated and managed following best
 medical practice with particular attention paid to patient safety, assessment of
 potential treatment-related adverse events, and changes in clinical status.

 EVALUATIONS: Study patients will be closely monitored throughout the study for safety
 and clinical response. The results of all safety and efficacy evaluations must be
 recorded in the CRF and in the source documents.

 DESCRIPTION OF EVALUATIONS AND STUDY-SPECIFIC PROCEDURES

 Informed Consent: Patients must give written informed consent, after the nature of the
 study has been fully explained, in order to participate in this study. No study-specific
 procedures may be performed before written informed consent is obtained.

 Randomization of Patients: Patients who sign an Informed Consent Form (ICF), complete
 all screening evaluations, pre-randomization (qualification) evaluations, and meet all
 entry criteria, will be eligible for randomization, and enrollment into the study.
 Randomization should occur within 2 days prior to study drug administration. All
 patients will be randomized in a 1:1:1 fashion to 1 of 3 treatment groups in order to
 reduce selection bias. All randomization will be managed centrally, by the GCRC.

 Medical and Medication History: A complete record of the patient's medical history,
 other medical conditions, and concomitant medications (including current lipid
 modification agents) will be obtained and recorded in the medical chart and CRF.

 Physical Examination, Vital Signs, and Weight: Patients will be seen by an Investigator
 for a complete physical examination, vital signs (temperature, systolic and diastolic
 blood pressure, pulse, and respiration rate), waist measurement and weight. Height will
 be measured at baseline only. The eye examination, including a funduscopic exam and
 measurement of visual acuity, will be conducted at the Baseline Visit and End of
 Treatment Visit only.

 Thyroid Symptom Assessment: Three clinical symptom scales (Hyperthyroid Symptom Scale,60
 Modified Billewicz Index for Hypothyroidism,61, 62 and the Hypothyroid Symptom Scale)
 will be used to assess and document potential thyroid-related symptoms. See attachment B
 for details. The hypothyroid scale is a patient self-assessment and will be completed by
 the patient at the beginning of the visit. The hyperthyroid scale and modified Billewicz
 will be completed by the Investigator or designee. The same scales are currently in use
 in the ongoing DITPA studies.

 Echocardiogram: An echocardiogram will be performed at Baseline and Visit 8/End of
 Treatment Visit for safety monitoring. The echocardiograms will be interpreted by a
 designated study cardiologist for safety and efficacy, in a blinded fashion.

 Electrocardiogram (ECG): An electrocardiogram should be performed at the specified
 visits.

 DEXA Scan: Dual Energy X-ray Absorptiometry, or DEXA scanning, will be used to measure
 bone mineral density and body fat composition.

 Laboratory Evaluations:

 The following laboratory testing will be performed according to the schedule in Appendix
 A:

 Hematology Hemoglobin, Hemoglobin A1C, Hematocrit, RBC, MCV, MCH, RBC Morphology, WBC
 with differential, and platelets Chemistry Total Bilirubin, Alkaline Phosphatase, ALT
 (SGPT), AST (SGOT), GGT, LDH, Urea Nitrogen (BUN), Creatinine, Creatinine Kinase,
 fasting Glucose, Serum Calcium, Phosphorus, Total Protein, Albumin, Sodium, Uric Acid,
 Potassium, HCO3, Amylase, and Chloride Urinalysis Blood, nitrites, protein, ketones,
 glucose, pH, and specific gravity Pregnancy test Human chorionic gonadotropin (HCG)
 assay Thyroid Function Tests Total T3, Total T4, and TSH Fasting Lipid Panel Low-density
 lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol,
 triglycerides, and total cholesterol Other lipids and future testing* Lipoprotein (a),
 apolipoprotein A, apolipoprotein B, lipoprotein subfractions by NMR spectroscopy,
 homocysteine, selectins, interleukins, PAI-1, myeloperoxidase, matrix
 metalloproteinases, leptin, adiponectin.

 PT/INR Prothrombin time/international normalized ratio Bone marker* Serum osteocalcin
 and N-telopeptide Inflammatory markers* High Sensitivity CRP (hs CRP) Analysis for DITPA
 concentrations* Trough steady state levels of DITPA * Testing of samples for these
 parameters may be performed at a later time, following initial efficacy analysis

 Fasting: Patients will be instructed to fast at least 12 hours prior to Visits 1, 2, 3,
 5, 6, 8, and 9 for the fasting lipid panel blood draws.

 Blood draws for DITPA concentrations: Blood for DITPA concentrations will be drawn at
 least 6 hours after the preceding dose of study drug. It is recommended that if the
 patient has a morning appointment, the patient should not take the morning dose until
 after the blood draw. If the patient has an afternoon appointment, the patient should
 take the morning dose as usual. The time of the preceding dose should be recorded in
 source documents and the CRF.
Inclusion Criteria:

 Patients are eligible for study entry based on the following criteria:

 1. Males or females greater than or equal to 18 years of age

 2. Females must not be pregnant or lactating. Females of childbearing potential and males
 must use a reliable means of contraception.

 3. LDL-C level greater than the NCEP goals, as determined by patients' risk category
 according to NCEP ATP III criteria

 4. Risk category for coronary heart disease and coronary heart disease equivalent with
 LDL goal of < 100 mg/dL

 5. Baseline lipid criteria: LDL-C = 100 to160 mg/dL and triglyceride level = 100 to 500
 mg/dL

 6. Normal thyroid function tests (total T3, total T4, and thyroid-stimulating hormone
 [TSH])

 7. Hemoglobin A1C < 8.5% on a stable oral hypoglycemic or insulin regimen

 8. On stable lipid modification pharmacotherapy (including a statin) for at least 2 weeks
 prior to study entry. Patients must be on at least half of the maximal doses of
 statins (as assessed by the Investigator), or be intolerant to statins such that the
 doses are not achievable.

 9. Able to give informed consent

 Exclusion Criteria:

 Pre-Randomization Exclusion Criteria

 Patients will not be eligible for the study based on the following criteria:

 1. History of thyroid disorders of any form within 24 weeks prior to study entry

 2. Active liver disease and/or liver transaminases greater than 1.5 X upper limit of
 normal

 3. Active myocarditis, hypertrophic cardiomyopathy, uncorrected primary valvular disease,
 restrictive cardiomyopathy, uncorrected congenital heart disease, or constrictive
 pericarditis

 4. Myocardial infarction, unstable ischemic heart disease, stroke, or coronary
 revascularization procedure within 24 weeks prior to study entry

 5. Moderate or severe symptomatic congestive heart failure (New York Heart Association
 class III and IV)

 6. Drug or alcohol dependence, or other conditions which may affect study compliance

 7. Renal insufficiency (serum creatinine > 2 mg/dL)

 8. Subjects taking other hormonal therapies (other than oral contraceptive agents and
 postmenopausal hormone replacement therapy) e.g., glucocorticoids, androgens, or
 growth hormones

 9. Use of thyroid supplements (levothyroxine, liothyronine, etc.) or any preparation
 containing thyromimetic agents within 24 weeks prior to study entry

 10. History of coagulopathy or use of anticoagulants such as warfarin

 11. Unstable endocrine/metabolic syndrome that may affect lipid metabolism

 12. History of atrial or ventricular arrhythmia

 13. Diagnosis of other non-cardiac underlying medical conditions expected to impact
 mortality within 24 weeks after randomization