E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heterozygous Familial Hypercholesterolaemia |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10058108 |
E.1.2 | Term | Dyslipidaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057099 |
E.1.2 | Term | Heterozygous familial hypercholesterolaemia |
E.1.2 | System Organ Class | 100000004850 |
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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 |
1. To compare the pharmacokinetics of laropiprant following administration of a single dose of 1 (Panel A) and 2 (Panel B) combination tablets of MK-0524A between adolescents with heterozygous familial hypercholesterolemia and healthy adults 2. To compare the total urinary excretion of niacin and niacin metabolites (sum of NA, NUA, MNA, 2PY) following administration of a single dose of 1 (Panel A) and 2 (Panel B) combination tablets of MK-0524A in adolescents with heterozygous familial hypercholesterolemia with healthy adults 3. To compare the pharmacokinetics of nicotinuric acid (NUA) following administration of a single dose of 1 (Panel A) and 2 (Panel B) combination tablets of MK-0524A in adolescents with heterozygous familial hypercholesterolemia with healthy adults 4. To evaluate the safety and tolerability following administration of a single dose of 1 (Panel A) and 2 (Panel B) combination tablets of MK-0524A in adolescents with heterozygous familial hypercholesterolemia.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient is a male or female post-pubertal adolescent subject of age 10-16 with heterozygous familial hypercholesterolemia: 2. Patient’s Height and weight fall between the 10th and 95th percentile for age with a minimum body weight of 23 kg at the screening visit. 3. The patient has LDL-C values ≥110 mg/dL (2.85 mmol/L) and ≤400 mg/dL (10.3 mmol/L) 4. Patient triglyceride (TG) values ≤400 mg/dL (4.52 mmol/L) 5. Patient has heterozygous familial hypercholesterolemia defined as: -(a) A known (documented) mutation in a copy of the patient’s LDL receptor or Apo B genes OR - (b) In the absence of genetic diagnosis, a patient must have a documented history of one or more of the following: - --Untreated total cholesterol (TC) ≥350 mg/dL (9.1 mmol/L) – --Untreated LDL-C ≥190 mg/dL (5.2 mmol/L) OR -(c) In the absence of the above diagnostic criteria, a patient must have documented history of one or more of the following: Either: -- Untreated LDL-C ≥160 mg/dL (4.1 mmol/L), or – --LDL-C ≥130 mg/dL (3.4 mmol/L) despite usual and stable lipid lowering therapy In combination with: - Documented history or presence of tendonous or cutaneous xanthoma in the patient or a first-degree relative - Documented history or presence of a mutated copy of the LDL receptor or ApoB gene in a parent - Presence in a first-degree adult relative of documented, untreated TC ≥350 mg/dL (9.1 mmol/L) or LDL-C ≥190 mg/dL (4.9 mmol/L) - Presence in a first-degree relative < 18 years of age of documented, untreated TC ≥280 mg/dL (7.2 mmol/L) or LDL-C ≥160 mg/dL (4.1 mmol/L) - Documented history of parent with premature coronary artery disease or sudden death from natural causes prior to the age of 55 years for a male and 60 years for a female For patients on lipid lowering medication, the untreated values of TC and LDL-C [inclusion 5. (b) and (c)] do not need to be met at screening. 6. Patient receives appropriate medical care for their hypercholesterolemia, such as a statin or other lipid-modifying therapy. Patients on a statin or any other lipid modifying therapy must be on a stable regimen for 6 weeks prior to the screening visit. 7. Glycemic status of the patient has been determined prior to randomization 8. Patient is judged to be in good health based on medical history, physical examination, vital sign measurements, and laboratory safety tests performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug. 9. Patient has no clinically significant abnormality on electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug. 10. Parent/legal guardian and patient understand the study procedures and agree to participate in the study as indicated by parental/legal guardian signature on the subject consent. 11. Patient is willing to comply with the study restrictions
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E.4 | Principal exclusion criteria |
1. Patients with a history of psychiatric or personality disorders that in the opinion of the investigator and sponsor, affects the patient’s ability to participate in the trial. 2. Patient has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the patient by their participation in the study. 3. Patient has an estimated creatinine clearance of ≤ 80 mL/min based on the Schwartz equation. An actual creatinine clearance, as determined by a 24-hour urine collection, may be used in place of, or in conjunction with, the Schwartz equation. 4. Patient has a history of stroke, chronic seizures, or major neurological disorder. 5. Patient has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases (excluding lipid abnormalities). Patients with a history of uncomplicated kidney stones or childhood asthma may be enrolled in the study at the discretion of the investigator. 6. Patient has Type 1 or Type 2 diabetes mellitus and: - is poorly controlled (HbA1C at Visit 1 >8%) or is newly diagnosed (within 3 months of Visit 1) - has recently experienced repeated hypoglycemia or unstable glycemic control. - is taking new or recently adjusted anti-diabetic pharmacotherapy within 3 months of Visit 1. 7. Patient has a history of neoplastic disease within 5 years from screening 8. Patient has LDL-C < 160 mg/dL (≤ 4.1 mmol/L) after dietary treatment 9. Patient consumes alcohol. 10. Patient consumes excessive amounts, defined as greater than 4 servings (1 serving is approximately equivalent to 120 mg of caffeine) of cola, coffee, tea, or other caffeinated beverages per day. 11. Patient has had major surgery, donated and/or received blood as follows: - Donated blood products or lost >300 mL within 8 weeks prior to signing the consent form - Intends to give or receive blood products during the study - Intends to donate more than 250 mL of blood products within 8 weeks following the follow-up visit 12. Patient has participated in another investigational study within 4 weeks prior to the prestudy (screening) visit. The 4 week window will be derived from the date of the last study procedure (i.e. poststudy, AE follow-up, etc.) in the previous study to the prestudy/screening visit of the current study. 13. Patient has a history of significant multiple and/or severe allergies (including latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food. 14. Patients who are positive for hepatitis B surface antigen, hepatitis C antibodies or HIV cannot be enrolled. 15. The patient cannot swallow large tablets. 16. There is any concern by the investigator regarding the safe participation of the patient in the study or for any other reason, the investigator considers the patient inappropriate for participation in the study. 17. Patient has the following age-specific exclusionary laboratory values at screening: - ALT (SGPT) >1.5 x upper limit of normal (ULN) - AST (SGOT) >1.5 x ULN - CK > 50% ULN - TSH >20% ULN - Platelet count <100,000/mm3 18. Patient is a nursing mother
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Plasma Area Under the Concentration Curve From 0 to Infinity (AUC0-∞) of Laropiprant 2. Plasma Maximum Concentration (Cmax) of Laropiprant 3. Total Urinary Excretion of Niacin and Niacin Metabolites 4. Plasma Cmax of Nicotinuric Acid (NUA)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Time Frame: Predose Day 1 up to 24 hours postdose 2. Time Frame: Predose on Day 1 up to 48 hours postdose 3. Time Frame: Predose on Day 1 up to 72 hours postdose 4. Time Frame: Predose on Day 1 up to 48 hours postdose
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Pediatric Pharmocokinetic |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
Will this trial be conducted at a single site globally?
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E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
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.8.9.2 | In all countries concerned by the trial months | 9 |