The primary objective of this study is to compare the efficacy of pitavastatin 1 mg once daily (QD), 2 mg QD, and 4 mg QD (after up-titration) to placebo in terms of the percentage reduction in LDL-C in children or adolescent patients with high-risk…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
hyperlipidemie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint of this study is the percent change in LDL-C from
baseline to Week 12 endpoint.
Secondary outcome
The secondary efficacy endpoints of this study are the following:
- Percent change in LDL-C from baseline over 12 weeks of treatment (Week 4,
Week 8, and Week 12);
- Percentages of patients who achieve AHA minimal (130 mg/dL [3.4 mmol/L]) and
ideal (110 mg/dL [2.8 mmol/L]) LDL-C targets over 12 weeks of treatment;
- Percent changes in HDL-C, non-high-density lipoprotein cholesterol
(non-HDL-C), TC, TG, apolipoprotein A1 (Apo A1), and Apo B from baseline over
12 weeks of treatment; and
- Changes in TC:HDL-C ratio, non-HDL-C:HDL-C ratio, and Apo B:Apo A1 ratio
from baseline over 12 weeks of treatment.
Background summary
Elevated serum cholesterol, particularly low-density lipoprotein cholesterol
(LDL-C), and its associated apolipoprotein B (Apo B), constitute a risk factor
for the development of coronary heart disease (CHD). It is now well established
that the atherosclerotic process begins in childhood. Based on the data in
adults demonstrating reduced incidence of CHD with statin-induced LDL-C
reduction, it is recommended that children considered at high risk for the
development of premature CHD should start drug therapy during childhood.
Statins, or 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase
inhibitors, are considered the drug of choice among adult patients with
elevated LDL-C and therefore are often considered for use in the paediatric
population.
The efficacy and safety data in the paediatric population are not as extensive
as in the adult population, but statins have been shown to be an effective
option for the management of childhood hypercholesterolaemia.
Pitavastatin calcium (pitavastatin) is a synthetic HMG-CoA reductase inhibitor
currently approved for marketing in several countries. Pitavastatin is
indicated as an adjunctive therapy to diet to reduce elevated total cholesterol
(TC), LDL-C, triglycerides (TG), and Apo B as well as to increase high-density
lipoprotein cholesterol (HDL-C). Overall, pitavastatin has been shown to be
safe and well tolerated in the adult population. Although the safety and
efficacy of pitavastatin are well documented in adults, the use of this drug
has not been studied in a paediatric population. Therefore, the goal of this
study is to evaluate the safety and efficacy of pitavastatin in children or
adolescent patients with high-risk hyperlipidaemia. The results of this study
will complement the existing body of knowledge obtained from clinical studies
of pitavastatin in adults and will be used to support broadening the indication
of pitavastatin to allow for use in children and adolescents.
Study objective
The primary objective of this study is to compare the efficacy of pitavastatin
1 mg once daily (QD), 2 mg QD, and 4 mg QD (after up-titration) to placebo in
terms of the percentage reduction in LDL-C in children or adolescent patients
with high-risk hyperlipidaemia at steady state (Week 12).
The secondary objectives of this study are the following:
- To compare the efficacy of pitavastatin 1 mg QD, 2 mg QD, and 4 mg QD to
placebo in terms of the change or percent change in secondary lipid parameters
in children and adolescent patients with high-risk hyperlipidaemia over 12
weeks;
- To measure PK parameters at each dose level; and
- To compare the safety and tolerability of pitavastatin 1 mg QD, 2 mg QD, and
4 mg QD to placebo in children and adolescent patients with high-risk
hyperlipidaemia over 12 weeks.
Study design
This is a double-blind, randomised, placebo-controlled, parallel-group study in
children and adolescent patients with high-risk hyperlipidaemia, excluding
patients with homozygous Familial Hypercholesterolaemia.
A Data Monitoring Committee (DMC) will be set up in accordance with EMEA
guidelines to oversee the safety of the participants of the study
Patients who use lipid lowering medications will undergo a 5-week wash-out
period.
After the screening visit (visit 1 or 2 depending on if a wash-out period is
necessary) randomization will take place. Recruitment will commence into the
pitavastatin 1 mg QD , Pitavastatin 2 mg QD and Placebo treatment groups
initially, until sufficient data has been collected to reassure the DMC that
the pitavastatin 4 mg QD (or placebo) dose group should be opened to
recruitment. Within each dose group patients will be assigned to Pitavastatin
and placebo in a 3:1 ratio.
The participants will receive treatment for 12 weeks. Patients who complete the
12-week treatment period will be eligible to enter a 52-week open-label
extension study (Study NK-104-4.02EU) to examine the long term tolerance of
pitavastatin.
The goal is to randomize 96 patients, including 40 patients in The Netherlands.
Intervention
Pitavastatin 1 mg QD (1mg pitavastatin) or placebo (matching placebo for 1 mg
pitavastatin) for 12 weeks. OR
Pitavastatin 2 mg QD (2 mg pitavastatin tablet) or placebo (matching placebo
for 2 mg pitavastatin) for 12 weeks. OR
Pitavastatin 4 mg QD (2 mg pitavastatin tablet for 4 weeks, 4 mg pitavastatin
tablet for 8 weeks) OR
placebo (matching placebo for 2 mg pitavastatin for 4 weeks, matching placebo
for 4 mg pitavastatin for 8 weeks).
To be taken orally, once-daily, with or without food, in the morning.
Study burden and risks
The adverse events that have been reported as 'common' in the current version
of the Investigator Brochure are:
Headache, Dizziness, Constipation, Diarrhoea, Dyspepsia, Nausea, Myalgia,
Arthralgia, changes in liverfunction test.
The patients will have 6 study visits, for which they will have to visit the
hospital. The following procedures will be performed:
- Medical history check (verbal) (1x)
- Physical examination (2x)
- ECG (2x)
- vital signs (incl height and weight) (5x)
- blood sampling:
Screening visit 1: 20.0 mL
Visit 3: 20.0 mL (without genotyping sample)
Visit 4: 12.0 mL
Visit 5: 12.0 mL (without PK)
Visit 6: 20.0 mL (without PK)
Total volume would therefore be: 84.0 mL
To be added with:
12.0 mL for washout patients that require visit 2
2 x 6.0 mL if a genetic sample is required
2 x 3.0 mL (trough + 1h post dose) for PK sample at visit
5 OR 6
3.0 mL per plasma myoglobin sample that will be taken as
needed
- urine sampling ( for pregnancy test, among other things) (6x for girls, 3x
for boys)
- diet assessment (6x)
- administration of study drug: daily for 12 weeks
105 Wharfedale Road
Winnersh Triangle, RG41 5RB, Wokingham,
US
105 Wharfedale Road
Winnersh Triangle, RG41 5RB, Wokingham,
US
Listed location countries
Age
Inclusion criteria
1. Male or female *6 years of age and <17 years of age at randomisation;;2. Have fasting LDL-C levels *160 mg/dL (4.1 mmol/L) or LDL-C *130 mg/dL (3.4 mmol/L) if any of the following additional risk factors are present:;* Male;;* A family history of premature cardiovascular disease defined as a myocardial infarction before age 50 in a second-degree relative or before age 60 in a first-degree relative with at least 1 relative (parent, grandparent, or sibling) affected;;* Presence of low HDL-C (<45 mg/dL) or high TG (>150 mg/dL);;* Presence of high lipoprotein(a) (>75 nmol/L);;09 December 2011 vii12;* Presence of type 2 diabetes mellitus diagnosed by treating physician according to current guidances; or;* Presence of hypertension defined as systolic and diastolic blood pressures above the 95th percentile for age and size;;3. Have not taken any lipid-lowering medications in the 5 weeks prior to screening or in the 4 weeks prior to the lipid qualifying visit at Week -1;;4. Have been adherent to an appropriate diet for at least 8 weeks;;5. Females who are post-menarche must not be pregnant or breast feeding and, if sexually active, must be using a reliable form of contraception; and;6. Written informed consent and assent (if necessary) obtained as required per local regulations.
Exclusion criteria
1. Unable or unwilling to take study drug;;2. Fasting TG >400 mg/dL (4.5 mmol/L);;3. Homozygous familial hypercholesterolaemia;;4. Other secondary causes of hyperlipidaemia (eg, hypothyroidism, human immunodeficiency virus infection, systemic lupus erythematosus, organ transplantation, previous malignancy, nephrotic syndrome, glycogen storage disease);;5. Previous history of statin intolerance, adverse effects with other statin use, or hypersensitivity to any components of the study drug;;6. Need for non-statin lipid-lowering medications;;7. Apheresis therapy;;8. Use of any concomitant medication which may interfere with the objectives of the study;;9. Type 1 diabetes mellitus;;10. Poorly controlled type 2 diabetes mellitus defined as haemoglobin A1c >9.0% at screening;;11. Severe renal impairment defined as serum creatinine >2.0 mg/dL at screening;;12. Uncontrolled hypertension;;13. Untreated thyroid disease;;14. Severe hepatic impairment, active liver disease, or persistent elevation of alanine transaminase or aspartate transaminase >3 × the upper limit of normal (ULN);;15. Active muscle disease or creatine kinase >3 × ULN (unless explained by exercise);;16. Screening laboratory values within the following age/gender appropriate reference ranges as assessed by the central laboratory:;* Haemoglobin <10 g/dL for males or <9 g/dL for females or;* Alkaline phosphatase >2 × ULN for age;;17. Any other laboratory abnormality that could compromise patient safety because of study participation;;18. Malignancy during the past 5 years;;19. Current smoker or history of drug or alcohol abuse;;20. Hospitalisation for any cause within 30 days prior to the administration of study drug;;21. History of major surgery in the 3 months prior to screening;;22. Any medical condition which, in the judgment of the Investigator, would jeopardize the evaluation of safety and/or constitute a significant safety risk to the patient; or;23. Participation in another clinical study involving an investigational drug during the course of this study or within 30 days prior to signing the informed consent/assent form for this study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004964-32-NL |
| CCMO | NL39387.018.12 |