E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of primary dyslipidemia |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058108 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | 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)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |