Study of 3,5-Diiodothyropropionic Acid (DITPA) in Hypercholesterolemic Patients

• Status: Terminated
• Trial end date: 2007-04-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Johns Hopkins University
• Treatments: 3,5-diiodothyropropionic acid

Criteria

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