LDL-Cholesterol Lowering Effect of KB2115 as Add on to Statin

Karo Pharma

Status and phase: Completed; Phase 2

Conditions: Dyslipidemia

Treatments: Drug: KB2115

Study type: Interventional

Funder types: Industry

Identifiers

NCT00593047

2007-004413-33

KBT004

Details and patient eligibility

About

Thyroid hormones are known to reduce cholesterol levels through regulation of a number of key enzymes involved in synthesis, degradation, and lipid transport. However, the currently marketed thyroid agonists are non-selective, and cannot be used for the treatment of hypercholesterolemia due to extrahepatic consequences of hyperthyroidism, especially on heart, bone, and muscle.

To take advantage of thyroid hormone effect on lipid metabolism for the treatment of hypercholesterolemia, it is necessary to develop a selective thyroid receptor agonist that can induce hyperthyroidism in the liver, while an euthyroid state is preserved in the extrahepatic tissue. KB2115 is a thyroid agonist developed to be liver selective.

The purpose of the study is to assess the efficacy and safety of KB2115 as add on therapy to low and middle doses of statin following 12 weeks of exposure compared to placebo. The aim of the study is to assess efficacy (LDL-cholesterol lowering effects) and safety of KB2115 at doses between 25 and 100 µg and to define a clinically relevant dose or dose range for future studies.

Enrollment: 180 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Signed informed consent

2. Males or females aged 18 to 75 years. Female patients must be non-fertile. To be considered as non-fertile, females must fulfil the following:

   • Non-nursing and non-pregnant 12 months prior to enrolment
   • Not of child bearing potential ie, either documented irreversible surgically sterile (bilateral oophorectomy or hysterectomy is acceptable, but not tubal ligation) or post-menopausal. Post-menopausal is defined as serum follicle-stimulating hormone (FSH) levels in the post-menopausal range combined with amenorrhea for more than 1 year in a woman above 50 years of age, or amenorrhea for more than 2 years below 50 years of age

3. Patients with hypercholesterolemia treated with stable doses of the below listed lipid lowering medication for at least 3 months prior to randomization

   • Atorvastatin not more than 20 mg/day or
   • Simvastatin not more than 40 mg/day

4. LDL-cholesterol > 3.0 mmol/L (Week -1)

5. Subject able and willing to comply with all study requirements

6. At randomization, diet as instructed by the investigator during the last 4 weeks prior to randomization and willingness to follow these instructions throughout the study

Exclusion criteria

1. Cholesterol lowering agents other than the defined statins
2. History of somatic or psychiatric disease/condition, which may interfere with the objectives of the study as judged by the investigator
3. Clinically significant illness or clinically relevant trauma within 2 weeks before the administration of the investigational product as judged by the investigator
4. Chronic (> 3 months) pain condition requiring daily medication with pain killers
5. Glycosylated haemoglobin (HbA1c) > 7.0%
6. Diabetes requiring medication other than metformin
7. Clinically abnormal physical findings and laboratory values as judged by the investigator and abnormal resting ECG, eg, QTc interval > 450 msec
8. Body Mass Index of ≥ 40 kg/m2
9. Resent history (< 3 month) of stroke or transient ischemic attacks
10. History of seizure disorder, except febrile convulsions
11. A current diagnosis of cancer, unless in remission
12. Blood pressure (BP) of > 160/95 mm Hg
13. History of cardiac arrhythmia, such as intermittent supraventricular tachyarrhythmia and atrial fibrillation
14. Unstable angina pectoris, myocardial infarction or coronary bypass graft surgery or percutaneous coronary intervention < 6 month before randomization
15. Congestive heart failure New York Heart Association Class > 2
16. Unstable or severe angina pectoris or peripheral artery disease
17. Known thyroid disease or thyroid biomarkers (TSH, T3, free T3, T4, free T4) outside reference range for normal at enrolment and at baseline
18. Positive urine pregnancy test in women at enrolment
19. Use of thyroid replacement therapy and hormone replacement therapy (including contraceptive pills) for last 3 months before randomization

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

---

180 participants in 4 patient groups, including a placebo group

1

Placebo Comparator group

Description:

Statin + placebo

Treatment:

Drug: KB2115

2

Experimental group

Description:

Statin + KB2115 dose 1

Treatment:

Drug: KB2115

3

Experimental group

Description:

Statin + KB2115 dose 2

Treatment:

Drug: KB2115

4

Experimental group

Description:

Statin + KB2115 dose 3

Treatment:

Drug: KB2115