E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether 80 mg (2x40 mg) of the new formulation atorvastatin calcium chewable tablets were bioequivalent
to 80 mg of the commercial atorvastatin calcium tablet formulation Lipitor
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of atorvastatin
in different formulations in healthy volunteers.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Healthy male and/or female subjects between the ages of 18 and 55 years, inclusive (healthy was defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure [BP] and pulse rate measurement, 12-lead electrocardiogram [ECG] and clinical laboratory tests).
2. Body mass index (BMI) of 18 to 30 kg/m2; and a total body weight >45 kg (99 lbs). A BMI lower limit of 17.5 kg/m2 was permitted to be rounded up to 18.0 kg/m2; a BMI upper limit of 30.5 kg/m2 was permitted to be rounded down to 30.0 kg/m2 and was acceptable for inclusion.
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E.4 | Principal exclusion criteria |
1. Evidence or history of clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) disease or clinical findings at Screening.
2. Any condition possibly affecting drug absorption (eg, gastrectomy).
3. A positive urine drug screen.
4. History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for men (1 drink = 5 oz [150 mL] of wine or 12 oz [360 mL] of beer or 1.5 oz [45 mL] of hard liquor) within 6 months of Screening.
5. Subjects who smoke more than 5 cigarettes per day.
6. Treatment with an investigational drug within 30 days or 5 half-lives preceding the first dose of study medication.
7. 12-lead ECG demonstrating QTc >450 msec at Screening. If QTc exceeded 450 msec, the ECG was to be repeated two more times and the average of the three QTc values was to be used to determine the subject’s eligibility.
8. Pregnant or nursing females; females of childbearing potential who were unwilling or
unable to use an acceptable method of non-hormonal contraception from at least 14 days prior to the first dose of study medication.
9. Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever was longer) prior to the first dose of study medication. Herbal supplements and hormonal methods of contraception (including oral and transdermal contraceptives, injectable progesterone, progestin subdermal implants, progesterone-releasing intra-uterine device [IUDs], postcoital contraceptive methods) and hormone replacement therapy must be discontinued 28 days prior to the first dose of study medication. Depo-Provera® must be discontinued at least 6 months prior to the first dose of study medication. As an exception, acetaminophen/paracetamol could be
used at doses of ≤1 g/day. Limited use of non-prescription medications that were not believed to affect subject safety or the overall results of the study could be permitted on a case-by-case basis following approval by the sponsor.
10. Blood donation of approximately 1 pint (500 mL) within 56 days prior to dosing.
11. History of sensitivity to heparin or heparin-induced thrombocytopenia.
12. Unwilling or unable to comply with the Lifestyle guidelines described in the protocol.
13. Consumption of grapefruit or grapefruit-containing products within 7 days prior to the
first dose of study medication.
14. Subjects with serum creatine kinase levels >3x upper limit of normal.
15. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may have increased the risk associated with study participation or investigational product administration or may have interfered with the interpretation of study results and, in the judgment of the investigator, would have made the subject inappropriate for entry
into this study.
16. Have a known history of hypersensitivity, allergy (except for untreated, asymptomatic, seasonal allergies at the time of dosing), severe adverse drug reaction, or intolerance to atorvastatin or other statins.
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E.5 End points |
E.5.1 | Primary end point(s) |
AUClast, AUCinf (if data permitted), and Cmax from plasma atorvastatin concentration data. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
blood samples were collected before dosing on Day 1, and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36, 48,
and 72 hours after dosing
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E.5.2 | Secondary end point(s) |
Tmax and t1/2 (if data permitted) of atorvastatin; AUClast,AUCinf, Cmax, Tmax, and t1/2 (if data permitted) of ortho-hydroxyatorvastatin and
para-hydroxyatorvastatin.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
blood samples were collected before dosing on Day 1, and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36, 48,
and 72 hours after dosing
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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 | Yes |
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 | Yes |
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) | No |
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 | 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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
80 Mg Commercial Atorvastatin Calcium Tablet Formulation |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
Will this trial be conducted at a single site globally?
| Yes |
E.8.4 | Will this trial be conducted at multiple sites globally? | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
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 years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 24 |