This study is being conducted in patients with familial hypercholesterolaemia (FH) to: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 (…
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Source
Brief title
Condition
- Endocrine disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
The secondary endpoints will be the relative reduction in HDL cholesterol,
total cholesterol, ApoA1, ApoB, ApoB/ApoA1 ratio, and triglycerides between
Baseline and Week 6 and Week 12 and the differences between colesevelam and
placebo; changes in fasting glucose, HbA1c level and hsCRP at Week 6 and Week
12; the percentage of patients being below their target for LDL cholesterol of
2.5 mmol/L (100 mg/dL) at Week 6 and Week 12 (goal rate); the percentage of
patients with a relative reduction in their LDL cholesterol at Week 6 or Week
12 compared to Baseline of at least 15% or more (responder rate); and the
relative reduction of LDL cholesterol at 12 weeks compared to Baseline and the
difference between colesevelam and placebo.
Background summary
This is a prospective, randomised, double-blind, placebo-controlled,
parallel-group, multi-centre, Phase 4 study of colesevelam administered to
patients with FH as add-on therapy to a maximally tolerated and stable regimen
of a statin and ezetimibe on which their LDL cholesterol level is still above
their target (for either primary or secondary prevention).
Patients are known with FH, diagnosed by either presence of a documented
LDL-receptor mutation or a combination of several clinical diagnostic criteria
as described by Aalst-Cohen (van Aalst-Cohen, 2006, Eur Heart J) , based on a
combination of criteria from the United Kingdom (Simon Broome register
Criteria), The Netherlands (Dutch Lipid Clinic Network Criteria), and the USA
(MEDPED criteria). Patients will be considered in screening after they have
signed informed consent. Screening will comprise a 4 week run in period to
assess stability of the lipid lowering effect of the statin and ezetimibe
combination treatment patient has been on for at least 3 months. Patients will
be screened and after confirmation of suitability will return for the baseline
visit after a run-in period of 4 weeks. When the LDL cholesterol level at this
baseline visit is within 10% of the level at Screening, patients will be
randomised followed by start of daily treatment with colesevelam or placebo
during the Day 1 visit. Upon meeting study eligibility requirements at
Screening and Baseline, patients will be randomised to receive colesevelam or
placebo at 1:1 ratio (i.e., 40 patients per group), using a central
randomisation procedure, with stratification per site.
The investigational product consists of a daily dose of 6 tablets of
colesevelam (625 mg per tablet) or matching placebo tablets to be taken during
meals.
Dosing group Study treatment Total daily dose Total patients
1 colesevelam 6 tablets of 625 mg each 40
2 placebo 6 placebo tablets 40
Total 80
Patients will return for assessments at 6 weeks (±1 week) and 12 weeks (±1
week) after the Day 1 visit. After 12 weeks of blinded treatment all patients
will receive open colesevelam treatment and continue for another 40 weeks on
colesevelam. In the open treatment follow up period patients will have visits
at Weeks 18, 26, and 52. The duration of each patient*s participation in the
study will be maximal 13 months, inclusive of 4 week Screening and run-in
period and 3 months blinded treatment period and 9 month open treatment
follow-up. Safety and efficacy assessments will be performed at the designated
study visits. Adverse events (AEs) and concomitant medications will be
monitored and recorded throughout the study. Individual patients*
randomisation assignments will remain blinded until the last patient has
completed the 3 month blinded treatment period and the database with the 3
month data has been locked.
Study objective
This study is being conducted in patients with familial hypercholesterolaemia
(FH) to:
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.
2. Evaluate the safety and tolerability of colesevelam added to a maximal
tolerated and stable regimen of statin and ezetimibe.
Study design
This is a prospective, randomised, double-blind, placebo-controlled,
parallel-group, multi-centre, Phase 4 study of colesevelam administered to
patients with FH as add-on therapy to a maximally tolerated and stable regimen
of a statin and ezetimibe on which their LDL cholesterol level is still above
their target level. Target level for LDL cholesterol is based on the 2003
European Guidelines for lowering LDL cholesterol in high risk patients defined
as 2.5 mmol/L (100 mg/dL) (De Backer, 2003, Eur Heart J).
Patients with FH can be diagnosed by either presence of a documented
LDL-receptor mutation or a combination of several clinical diagnostic criteria
e.g., level of LDL cholesterol in patient and first degree relative and
presence of xanthomas or proven coronary artery disease in patient or first
degree relative, universally applied in the United Kingdom (Simon Broome
Register Criteria), The Netherlands (Dutch Lipid Clinic Network Criteria), and
the USA (MEDPED criteria) as described by van Aalst-Cohen (van Aalst-Cohen,
2006, Eur Heart J). A patient is considered to be in screening after he or she
has signed informed consent. Patient will be asked to swallow a test dose of
placebo tablets as part of the screening procedures to familiarise the patient
with the tablets used. Screening will comprise a 4 week run in period to
assess stability of the lipid lowering effect of the statin and ezetimibe
combination treatment the patient has been on for at least 3 months. At the
Baseline visit, it will be checked if LDL cholesterol level is within 10% of
that level at Screening. Upon meeting the Screening and Baseline study
eligibility requirements, patients will be randomised to receive colesevelam or
placebo at 1:1 ratio (i.e., 40 patients per group).
The investigational product consists of tablets of colesevelam (625 mg per
tablet) or matching placebo tablets. A total of 6 colesevelam or placebo
tablets should be taken every day with a meal, either 6 tablets once a day or 3
tablets twice a day. Patients will need to continue their maximal tolerated
dose of statins and ezetimibe.
The duration of each patient*s participation in the study will be maximal 13
months, inclusive of a 4 week Screening and run-in period, a 3 month double
blind treatment period a 9 month open treatment follow-up period. Patients
will return for assessments at Week 6 (± 1 week), Week 12 (± 1 week), Week 18
(± 1 week), Week 26 (± 2 weeks), and Week 52 (± 2 weeks) after the Day 1
visit. Safety and efficacy assessments will be performed at the designated
study visits.
Adverse events (AEs) and concomitant medications will be monitored and recorded
throughout the study. Individual patients* randomisation assignments will
remain blinded for the duration of the study until the last patient has
completed the 3 month double blind treatment period.
Intervention
One group will receive 6 tablets/day Colesevelam and one group will receive 6
tablets/day Placebo for a period of 12 weeks. This procedure is dubbel blind
Study burden and risks
minimum risk
Gooimeer 10
1411 DD Naarden
Nederland
Gooimeer 10
1411 DD Naarden
Nederland
Listed location countries
Age
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 (FH) 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 stable 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 at least 3 placebo tablets
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., hypothyroidism, nephrotic syndrome (defined as proteinuria >2 g/L), dysproteinaemias, 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 having 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., glycosylated haemoglobin (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 (New York Heart Association [NYHA] Class 3 or 4), life threatening ventricular arrhythmias, unstable angina, recent myocardial infarction within the past 6 month prior to screening or patients undergoing haemodialysis, or with active disease who may not be healthy enough to successfully complete all protocol requirements
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-000582-37-NL |
| CCMO | NL16666.018.07 |