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

A Phase II, Placebo-Controlled, Double-Blind, Randomised, 12-Week, Parallel-Group Study to Assess the Efficacy of Different Doses of KB2115 as Add on to Statin Treatment in Patients With Dyslipidemia

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.

Study Overview

• Status: Completed
• Conditions: Dyslipidemia
• Intervention / Treatment: Drug: KB2115

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Gothemburg, Sweden
    • Carl-Peter Anderberg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1; Statin + placebo	Drug: KB2115; tablet formulation given once daily for 12 weeks
Experimental: 2; Statin + KB2115 dose 1	Drug: KB2115; tablet formulation given once daily for 12 weeks
Experimental: 3; Statin + KB2115 dose 2	Drug: KB2115; tablet formulation given once daily for 12 weeks
Experimental: 4; Statin + KB2115 dose 3	Drug: KB2115; tablet formulation given once daily for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
LDL cholesterol	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Triglyceride	12 weeks

Collaborators and Investigators

• Sponsor: Karo Bio AB
• Investigators: Study Director: Jens Kristensen, MD, PhD, Karo Bio AB

Publications and helpful links

General Publications

• Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, Baxter JD, Angelin B. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010 Mar 11;362(10):906-16. doi: 10.1056/NEJMoa0905633.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: December 17, 2007
• First Submitted That Met QC Criteria: January 11, 2008
• First Posted (Estimate): January 14, 2008

Study Record Updates

• Last Update Posted (Estimate): December 1, 2008
• Last Update Submitted That Met QC Criteria: November 27, 2008
• Last Verified: May 1, 2008

More Information

Terms related to this study

• Keywords: hypercholesterolemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias
• Other Study ID Numbers: KBT004; 2007-004413-33