A Phase 4 Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Centre Study of Colesevelam as Add-on Therapy in Patients with Familial Hypercholesterolaemia

• Conditions: Familial hypercholesterolaemia; MedDRA version: 9.1Level: LLTClassification code 10049593Term: Familial hypercholesterolaemia

• Registration Number: EUCTR2007-000582-37-DE
• Lead Sponsor: Genzyme Europe BV

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2007-12-07
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Patients must be males or females between 18 and 75 years of age, inclusive

2. Patients must have a clinical diagnosis of Familial Hypercholesterolaemia defined as EITHER
a). Presence of a documented LDL-receptor mutation OR
b). History of untreated LDL-cholesterol level above the 95th percentile for sex and age in combination with documentation of at least one of the following
i. Presence of typical tendon xanthomas in the patient or first degree relative
ii. An LDL-cholesterol level above the 95th percentile for age and sex in a first degree relative
iii. Proven coronary artery disease in the patient or in a first degree relative under the age of 60

3. Patients must have been provided and undergone lifestyle changes for more than 6 months at time of Screening

4. Patients must have been treated for at least 3 consecutive months preceding the Screening visit with a lipid lowering treatment regimen consisting of a maximal tolerated combination of a statin with ezetimibe and are still above their target for LDL cholesterol being 2.5 mmol/L (100 mg/dL)

5. Patients must be committed to following the protocol requirements as evidenced by written informed consent

6. Patients should be comfortable with swallowing 3 placebo tablets

Baseline Inclusion Criteria:
Patients must have stable LDL cholesterol defined as variability of 10% or less between the Screening LDL cholesterol level and the Baseline LDL cholesterol level assessed at least 4 weeks after Screening. If the first Baseline level is not within the required 10% variability, a second Baseline level can be taken within two weeks, again for comparison to the Screening LDL cholesterol level.

In order to prevent a substantial screen failure rate due to the baseline inclusion criterion (a variability of 10% or less between the Screening LDL cholesterol level and the second Baseline LDL cholesterol level) the following conditions are set:

1. In case 4 of the first 10 patients screened in the study (i.e., 40%) are excluded from the study due to a variability of more than 10% between the Screening LDL cholesterol level and the second Baseline LDL cholesterol level, the baseline inclusion criterion will be changed to allow a difference of 15%.

2. In case 6 of the first 20 patients screened in the study (i.e., 30%) are excluded from the
study due to a variability of more than 10% between the Screening LDL cholesterol level and the second Baseline LDL cholesterol level, the baseline inclusion criterion will be changed to allow a difference of 15%.

When the baseline inclusion criterion is changed, sites are allowed to invite patients who were initially excluded based on a LDL cholesterol variability >10% and <15% for rescreening. These patients will be considered new patients and will therefore start the screening process from the beginning.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Patients with a known allergy to any of the components used in colesevelam or placebo or any other medications like statin or ezetimibe required for participation in this study

2. Patients with a bowel or biliary obstruction

3. Patients with secondary causes of hypercholesterolaemia, e.g., dysproteinaemia, hypothyroidism, nephrotic syndrome (defined as proteinuria > 2 g/L), obstructive liver disease, other pharmacological therapies, alcoholism

4. Patients with triglyceride level of > 3.4 mmol/L

5. Patients with dysphagia, swallowing disorders, severe gastrointestinal motility disorders, inflammatory bowel disease, or major gastrointestinal tract surgery

6. Patients have undergone LDL-apheresis within one year prior to the screening visit and/or need to undergo LDL-apheresis

7. Patients with active liver disease or unexplained persistent elevations in transaminases

8. Patients on fenofibrates or on concomitant cholestyramine as this will affect the area under the curve (AUC) of ezetimibe

9. Patients with poorly-controlled diabetes (i.e., HbA1c > 9% at Screening)

10. Patients with clinically significant (CS) abnormal haematology, renal, or other laboratory parameters that could be the result of an underlying malignancy or systemic infection as judged by the investigator

11. Patients with a heart transplant, concurrent congestive heart failure (NYHA Class 3 or 4), life-threatening ventricular arrhythmias, unstable angina, recent myocardial infarction within the past 6 months prior to screening, or patients undergoing haemodialysis, or with active disease who may not be healthy enough to successfully complete all protocol requirements

12. Fertile women who are pregnant, nursing or using either no or an inadequate form of contraception taking into account the recommendations for adequate intake of oral contraceptives as outlined in the concomitant medication section

13. Patients with a recent history of alcoholism or drug abuse, or severe emotional, behavioural or psychiatric problems who may not be able to adequately comply with the requirements of the study or who may be unable to consent

14. Patients receiving experimental medications or participating in another study using an experimental drug or procedure within 30 days of signing informed consent

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 1. Assess the efficacy of colesevelam added to a maximal tolerated and stable regimen of statin and ezetimibe in further decreasing the low-density lipoprotein (LDL) cholesterol level in terms of additional percentage decrease and in terms of reaching below target level of LDL cholesterol.<br><br>2. Evaluate the safety and tolerability of colesevelam added to a maximal tolerated and stable regimen of statin and ezetimibe.;Secondary Objective: ;Primary end point(s): The primary efficacy endpoint is the relative reduction in LDL cholesterol at Week 6 compared to Baseline and the difference between colesevelam and placebo. Baseline is defined as the LDL cholesterol level taken the closest in time to the Day 1 visit.