A double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of TAK-475 or placebo when co-administered with current lipid-lowering therapy in subjects with homozygous familial hypercholesterolemia

• Register: EUCTR
• Last refreshed on: 18 April 2012
• Main ID: EUCTR2005-003626-26-GB
• Date of registration: 01/11/2005
• Prospective Registration: Yes
• Primary sponsor: Takeda Europe R&D Centre Ltd
• Public title: A double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of TAK-475 or placebo when co-administered with current lipid-lowering therapy in subjects with homozygous familial hypercholesterolemia
• Scientific title: A double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of TAK-475 or placebo when co-administered with current lipid-lowering therapy in subjects with homozygous familial hypercholesterolemia
• Date of first enrolment: 14/06/2006
• Target sample size: 40
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-003626-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1. Subjects must be at least 8 years of age and weigh = 30kg

2. Subjects must have homozygous FH documented by genetic testing confirming 2
mutated alleles at the LDL-receptor locus or by the following clinical criteria (both
criteria must be satisfied):
• Subjects must have documented history of untreated fasting serum LDL > 460
mg/dL (11.91 mmol/L)
• Tendinous xanthomas and/or corneal arcus before 10 years of age and /or
premature coronary heart disease before 20 years of age.

3. Subjects must have read and understood the Subject Information Sheet / Informed Consent and signed the Informed Consent Form. If the subject is considered a minor, a minor assent form should be executed by the minor and a parent or legal guardian must also give their full consent in writing in accordance with applicable laws and regulations.

4. Subjects must have been taking a stable, approved lipid-lowering drug regimen for a minimum of 8 weeks prior to Screening Visit 1 and will continue to do so for the
duration of the study.

5. If female and of childbearing potential, the subject is not pregnant, not lactating, not planning on becoming pregnant and agrees to use adequate contraception (as defined in the informed consent form) between Screening Visit 1 and 30 days following the last dose of study medication.

6. The subject is capable of understanding and complying with protocol requirements.
Are the trial subjects under 18? yes
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. The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase
(AST) levels > 2 times the upper limit of normal (ULN), active liver disease,
jaundice, or serum creatinine > 135 µmol/L (1.5mg/dL) at screening.

2. The subject has a CPK > 3 times the ULN at screening. A repeat test for any of these tests described in the first two criteria is permitted and is at the discretion of the investigator.

3. The subject has a positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or subject’s verbal report.

4. The subject has a positive human immunodeficiency virus (HIV) status or is taking
antiretroviral medications, as determined by medical history and/or subject’s verbal
report.

5. The subject is unable or unwilling to discontinue excluded medications (see Section
7.4) or to continue stable doses of “stable dose” medications or would require treatment with any excluded medication during the study.

6. The subject is currently participating in another investigational study or has
participated in an investigational study within the past 30 days or, for drugs with a
long half-life, within a period of less than 5 times the drug’s half-life.

7. The subject has a previous history of cancer that has been in remission for less than 5 years prior to the first dose of study drug. This criterion does not include those subjects with basal cell or Stage 1 squamous cell carcinoma of the skin.

8. The subject has known hypersensitivity or history of adverse reaction to TAK-475.

9. The subject has a history of fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain.

10. The subject has an endocrine disorder, such as Cushing’s Syndrome,
hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid
metabolism. Subjects with hypothyroidism on appropriate replacement therapy
(defined as stable thyroid hormone replacement therapy at least 3 months prior to
Visit 1 and TSH levels < 1.5 x ULN) will be eligible for enrollment. If the subject’s
TSH is >1.5 x ULN, a free T4 level will be determined and if the free T4 is within
normal limits the subject may continue in the study.

11. The subject has uncontrolled hypertension despite medical treatment (defined for
adults as mean resting diastolic blood pressure >100 mm Hg or mean resting systolic
blood pressure >160 mm Hg) at Screening Visit 1.

12. The subject has inflammatory bowel disease or any other malabsorption syndrome or has had gastric bypass or any other surgical procedure for weight loss.

13. The subject has a history of drug abuse (defined as illicit drug use) or a history of
alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic
drinks per day) within the past 2 years.

14. The subject is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent (including minor assent) is available.

15. The subject has any other serious disease or condition at screening or at
randomization that might reduce life expectancy, impair successful management according to the protocol or make the subject an unsuitable candidate to receive
study drug.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Treatment of primary dyslipidemia
MedDRA version: 8 Level: PT Classification code 10058108

Intervention(s)

Product Name: TAK-475
Product Code: TAK-475
Pharmaceutical Form: Tablet
Current Sponsor code: TAK-475
Concentration unit: % percent
Concentration type: range
Concentration number: 95-105
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): The primary efficacy variable is the fasting plasma LDL-C concentration.

The secondary efficacy endpoints are the fasting plasma concentrations of the following
lipid variables:
• Total cholesterol (TC)
• Total triglycerides (TG)
• Very-low density lipoprotein cholesterol (VLDL-C)
• High-density lipoprotein cholesterol (HDL-C)
• Apolipoprotein A1 (Apo A1)
• Apolipoprotein B (Apo B)

Main Objective: The primary objective is to evaluate the effect of TAK-475 QD compared to placebo on low-density lipoprotein cholesterol (LDL-C) in subjects with HoFH when co-administered with current lipid-lowering therapy for 12 weeks.

Secondary Objective: To evaluate the safety and tolerability of TAK-475 compared to placebo during a 12-week double-blind treatment period when co-administered with current lipid-lowering therapy. The long-term safety of TAK-475 treatment in this population will continue to be evaluated during the open-label extension period. To evaluate the effect of TAK-475 compared to placebo on other lipid variables: total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), very-low density lipoprotein cholesterol (VLDL-C), lipoprotein (a), apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) during a 12-week double-blind treatment period.

Secondary ID(s)

01-05-TL-475-016