To assess the efficacy of rosuvastatin 20 mg on low-density lipoprotein cholesterol (LDL-C), compared to placebo, after 6 weeks of treatment in pediatric patients with HoFH.
ID
Source
Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
LDL-C following 6 weeks of treatment with rosuvastatin 20 mg or placebo
Secondary outcome
- LDL-C following 6 weeks of treatment with rosuvastatin 20 mg or placebo in
patients not treated with apheresis
- High-density lipoprotein cholesterol (HDL-C), total cholesterol (TC),
triglyceride (TG), non-HDL-C, LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C,
apolipoprotein B (ApoB), ApoB/apolipoprotein A-1 (ApoA-1) and ApoA-1 following
6 weeks of treatment with rosuvastatin 20 mg or placebo
- Change in LDL-C from end of placebo period to 6, 12, and 18 weeks of therapy
with rosuvastatin 20 mg
- Rosuvastatin trough concentrations
Background summary
Homozygous Familial Hypercholesterolemia is an inherited disorder most commonly
caused by mutations in the low-density lipoprotein (LDL) receptor gene. The
mutations mean that the LDL receptors don*t work properly resulting in high
cholesterol in the blood. The onset of all forms of atherosclerotic
cardiovascular disease can also be accelerated. The prevalence of HoFH is very
rare, occurring in about 1 in a million people worldwide. At this time no drug
is approved for treatment of HoFH in pediatric patients.
Study objective
To assess the efficacy of rosuvastatin 20 mg on low-density lipoprotein
cholesterol (LDL-C), compared to placebo, after 6 weeks of treatment in
pediatric patients with HoFH.
Study design
D3561C00004 is a randomized, double-blind, cross-over study of rosuvastatin 20
mg once daily (QD) versus placebo QD in children and adolescents (aged from 6
to <18 years) with homozygous familial hypercholesterolemia (HoFH).
The study aims to enroll approximately 25 patients to provide an estimated 20
patients to complete the study.
Patients will qualify for the study by meeting all inclusion and none of the
exclusion criteria at screening (Visit 1). Once eligibility is reconfirmed
(Visit 2), patients will discontinue all lipid-lowering medication, with the
exception of ezetimibe, and will be administered 10 mg rosuvastatin QD in a
4-week dietary lead-in phase. Patients who enter the study taking 20 mg or more
of rosuvastatin will be administered rosuvastatin 20 mg in the lead-in phase.
Patients who enter the study on ezetimibe therapy will be allowed to continue
the medication throughout the entire study. The dose of ezetimibe should remain
stable from the start of the lead-in phase (Visit 2) through the end of the
efficacy maintenance phase. At the end of the rosuvastatin lead-in phase (Visit
3), patients will be randomized 1:1 to one of two treatment sequences: A or B.
Treatment sequence A consists of 6 weeks of treatment with rosuvastatin 20 mg
QD followed by 6 weeks of placebo QD. Treatment sequence B consists of 6 weeks
of placebo QD followed by 6 weeks of treatment with rosuvastatin 20 mg QD.
Patients who enter the study taking 10 mg or more of rosuvastatin, and who do
not require discontinuation of any lipid-lowering medication, will be asked to
begin the dietary lead-in at the screening visit. Once eligibility is
reconfirmed at the second visit, these patients will be permitted to forego the
lead-in phase of the study and may proceed directly to the randomized,
cross-over phase of the study.
Blood samples will be drawn at the end of each 6 week period in the cross-over
phase (Visit 4 and Visit 5). The randomized, cross-over phase will be followed
by a 12-week efficacy maintenance phase, during which all patients will receive
rosuvastatin 20 mg QD. Blood samples will be drawn after 6 weeks of the
efficacy maintenance phase (Visit 6) and at the end of the 12 week efficacy
maintenance phase (Visit 7).
For patients who undergo apheresis, it is optimal to have blood drawn at least
7 days following the last apheresis. Because of the rapid changes that occur in
LDL-C levels following apheresis, it is very important to ensure that blood
samples taken during the 2 cross-over periods (and during the efficacy
maintenance phase) are scheduled to be drawn the same number of days following
the last apheresis and at the same time of the day in relation to the last
apheresis. If patients are on a regular schedule for apheresis, eg, every 1 or
2 weeks, blood samples should be drawn in association with the apheresis, and
must be obtained before (not after) the apheresis procedure.
After the efficacy maintenance phase, patients will have the opportunity to
continue treatment in a separate Long Term Extension (LTE) study expected to
extend through 2016.
Intervention
At the end of the lead-in phase of rosuvastatin (visit 3), the patients will be
randomized 1:1 to one of the two treatment groups: A or B. Treatment group A
consists of a treatment of 6 weeks with rosuvastatin 20 mg QD, followed by 6
weeks placebo QD. Treatment group B consists of 6 weeks placebo QD, followed by
6 weeks treatment with rosuvastatine 20 mg QD.
Study burden and risks
Nature and extent of the burden and risks for the patient:
- To read and sign the consent form and the assent form
- Visit the hospital on fixed timepoints
- Not taking certain medications during the study (e.g. prescription
medications)
- To fast (no eating and no drinking, only water) for at least 12 hours before
each visit
- To follow the fixed study procedures
- Regular collection of blood
Possible side effects of study drug:
Common (*1/100, <1/10) Headache, myalgia, asthenia, constipation, dizziness,
nausea, abdominal pain, diabetes mellitus*.
Uncommon (*1/1000, <1/100) Pruritus, rash and urticaria.
Rare (*1/10000, <1/1000) Myopathy (including myositis), hypersensitivity
reactions (including angioedema), rhabdomyolysis,
pancreatitis.
Risk of the study procedures:
- Blood samples: faintness, inflammation of the vein, pain, bruising or
bleeding at the site of the puncture. There's also a slight possibility of
infection
- ECG: skin irritation
In order to ensure that the potential side effects are diagnosed by the doctor
as early as possible, it is asked to report any muscle pain or weakness the
child experiences during the treatment. Especially if the child feels unwell,
has a fever or has reddish brown urine.
The patient may, or may not, benefit from participation in this study but
information retrieved from this study can be of added value for the medical
knowledge in this area and can help to develop a better treatment for people in
the future.
Pepparedsleden 1
Mölndal 431 83
SE
Pepparedsleden 1
Mölndal 431 83
SE
Listed location countries
Age
Inclusion criteria
1. Prior to any study-related procedures being performed, provision of written
informed consent from a parent/both parents or guardian and statement of assent
from the child or adolescent (if required by Institutional Review Board [IRB] or
Independent Ethics Committee [EC] according to local regulations and guidelines).
Communication between the Investigator, patient/guardian and child/adolescent to
confirm understanding and required compliance with the requirements of the study;
2. Male and female children and adolescents (aged 6 to <18 years) with at least 1 of
the following criteria:
* Documentation of genetic testing confirming 2 mutated alleles of either the
LDL receptor gene locus, ApoB, or PCSK9; and/or
* Documented untreated LDL-C >500 mg/dL (12.9 mmol/L) and triglyceride
(TG) <400 mg/dL (4.5 mmol/L) and at least 1 of the following criteria:
o Tendinous and/or cutaneous xanthoma prior to 10 years of age; or
o Documentation of HeFH in both parents by:
* genetic and/or
* clinical criteria;
3. Negative pregnancy test (b-human chorionic gonadotropin analysis) prior to
baseline in females of child-bearing potential:
* Female patients of child-bearing potential must adhere to a pregnancy
prevention method (abstinence, chemical, or mechanical) during the study and
3 months following the last dose;
* Male patients should refrain from fathering a child (including sperm donation)
during the study and up to 3 months following the last dose; and
4. Willing to follow all study procedures including adherence to dietary guidelines,
study visits, fasting blood draws, and compliance with study treatment regimens.
Exclusion criteria
1. History of statin-inducted myopathy or serious hypersensitivity reaction to other
HMG-CoA reductase inhibitors (statins), including rosuvastatin, at Visit 1;
2. Fasting serum glucose of >9.99 mmol/L (180 mg/dL) or glycosylated hemoglobin
>9% at Visit 1 or patients with a history of diabetic ketoacidosis within the past
year;
3. Uncontrolled hypothyroidism defined as thyroid stimulating hormone (TSH)
>1.5 times the upper limit of normal (ULN) at Visit 1 or patients whose thyroid
replacement therapy was initiated or modified within the last 3 months prior to
Visit 2;
4. Current active liver disease or hepatic dysfunction (except a confirmed diagnosis of
Gilbert*s disease) as defined as ALT or AST elevations of 2 times the ULN for any
age, or bilirubin elevation of 1.5 times the ULN for any age at Visit 1;
5. Serum CK *3 times ULN (unless explained by exercise) at Visit 1. If CK *3 times
ULN is assessed to be explained by exercise, retesting may be performed at Visit 2;
6. Estimated glomerular filtration rate by Schwartz formula <50 mL/min at Visit 1;
7. A *2+ proteinuria on urine dipstick at Visit 1;
8. Stage 2 hypertension (systolic and/or diastolic blood pressure greater than 5 mmHg
above the 99th percentile for age, gender, and height) at Visit 1;
9. History of solid organ transplantation at Visit 1;
10. Involvement in the planning and/or conduct of the study (applies to both
AstraZeneca staff and representatives and/or staff at the study site);
11. Previous randomization in the present study;
12. Participation in a clinical study where an investigational product was ingested
during the last 30 days before Visit 2 of the current study;
13. Any clinically significant acute illness within 2 weeks before the start of the study
(Visit 1);
14. Any clinically significant abnormalities in clinical chemistry, hematology, or
urinalysis results at the discretion of the Investigator;
15. Any contraindication from the following: a detailed medical and drug history, a
complete physical examination including vital signs, blood chemistry, hematology,
coagulation factors, and urinalysis;
16. Definite or suspected personal history or family history of clinically significant
adverse drug reactions (ADRs), or hypersensitivity to drugs with a similar chemical
structure to rosuvastatin as well as other statins;
17. History or presence of gastrointestinal, hepatic, or renal disease or other condition
known to interfere with absorption, distribution, metabolism, or excretion of drugs;
18. Treatment in the previous 3 months with any drug known to have a well-defined
potential for hepatotoxicity (eg, halothane);
19. Clinical judgement by the Investigator that the patient should not participate in the
study;
20. Patients weighing <20 kg (44 lbs);
21. Pregnancy or currently lactating; or
22. Patients planning to start apheresis during the study period.
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 | EUCTR2014-000972-24-NL |
| CCMO | NL49434.018.14 |