E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Vorapaxar is indicated for the reduction of thrombotic cardiovascular
events in patients with a history of myocardial infarction (MI) or with
peripheral
arterial disease (PAD). |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014501 |
E.1.2 | Term | Embolism - blood clot |
E.1.2 | System Organ Class | 100000004866 |
|
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 evaluate the comparative bioavailability between:
• MK-5348 (vorapaxar) 0.2085 mg/mL oral suspension from Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., USA; and
• MK-5348 (Zontivity™) 2.08 mg tablet (equivalent to 2.5 mg
vorapaxar sulfate) from Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., USA; after a single-dose in healthy subjects under
fasting conditions. |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Healthy, non-smoking, male and female subjects, from 18 to 55
years of age.
2) BMI ≥ 19.0 and ≤30.0 kg/m2 and weight ≥60 kg.
3) No clinically significant findings in vital-signs measurements.
4) No clinically significant abnormal laboratory values.
5) No clinically significant findings in a 12-lead electrocardiogram
(ECG).
6) Have no significant diseases.
7) Willing to use an acceptable, effective method of contraception.
8) Be informed of the nature of the study and give written consent
prior to any study procedure.
9) Have no clinically significant findings from a physical examination. |
|
E.4 | Principal exclusion criteria |
1) Known history or presence of any clinically significant medical
condition.
2) Known or suspected carcinoma.
3) History of stroke, myocardial infarction (MI), transient ischemic
attack (TIA), peripheral arterial disease (PAD) or intracranial
hemorrhage (ICH).
4) Known history or presence of active clinically
significant/pathological bleeding (e.g., peptic ulcer, intracranial
hemorrhage, clotting disorders).
5) Known history or presence of galactose or fructose intolerance,
sucrase-isomaltase insufficiency, Lapp lactase insufficiency,
galactosemia, or glucose-galactose malabsorption syndrome.
6) Subjects with mouth piercings, dentures, braces, dental appliances,
or any other alteration to the mouth that may compromise drug
delivery.
9) Presence of clinically significant gastrointestinal disease or history
of malabsorption within the last year.
10) Presence of a medical condition requiring regular medication
(prescription and/or over-the-counter) with systemic absorption.
11) History of drug or alcohol addiction requiring treatment.
12) Positive test result for HIV, Hepatitis B surface antigen or Hepatitis
C antibody.
13) Positive test result for urine drugs of abuse (cannabinoids, opiates,
amphetamines, cocaine, phencyclidine, tricyclic antidepressants,
barbiturates, methadone and benzodiazepines) or urine cotinine.
14) Difficulty fasting or consuming standard meals.
15) Does not tolerate venipuncture.
16) Use of tobacco or nicotine-containing products within 6 months
prior to drug administration.
17) On a special diet within 30 days prior to drug administration (e.g.,
liquid, protein, raw food diet).
18) Participated in a clinical trial, which involved administration of an
investigational medicinal product within 30 days prior to drug
administration, or recently participated in a clinical investigation that,
in the opinion of the Investigator, would jeopardize subject safety or
the integrity of the study results.
19) Donation or loss of whole blood (including clinical trials):
• ≥ 50 mL and ≤ 499 mL within 30 days prior to drug administration;
• ≥ 500 mL within 56 days prior to drug administration.
20) Females who:
• Have used oral or transdermal hormonal contraceptives within 21
days prior to drug administration;
• Have used implanted, injected, intravaginal or intrauterine hormonal
contraceptives within 6 months prior to drug administration;
• Are pregnant (serum hCG consistent with pregnancy); or
• Are lactating.
21) Have had a tattoo or body piercing within 30 days prior to drug
administration.
22) Estimated creatinine clearance of ≤80 mL/min based on the
Cockcroft-Gault equation.
23) Known history or presence of hypersensitivity or idiosyncratic
reaction to vorapaxar (MK-5348) or any other drug substances with
similar activity.
24) Subject is mentally or legally incapacitated, has significant
emotional problems at the time of screening or expected during the
conduct of the study or has a history of a clinically significant
psychiatric disorder over the last 5 years. Subjects who have had
situational depression may be enrolled in the study at the discretion of
the investigator.
25) Have planned a surgery or dental procedure within 30 days after drug administration.
26) Within 30 days prior to the drug administration, use of:
• antidepressants (e.g., SSRI [citalopram, fluoxetine], SNRI
[dexvenlafaxine, duloxetine]);
• antiplatelet, anticoagulants or fibrinolytics (e.g., acetylsalicylic acid,
clopidogrel, heparin, warfarin, acenocoumarol, dabigatran,
rivaroxaban, apixaban);
• chronic nonsteroidal anti-inflammatory drugs (NSAIDs);
• CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole,
clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir,
boceprevir, telaprevir, telithromycin, conivaptan) and
inducers (e.g., rifampin, carbamazepine, St. John's Wort, phenytoin);
• drugs known to alter gastrointestinal pH/movement (e.g.,
omeprazole, ranitidine).
27) 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.
7) History of any surgery on the oral cavity or throat in the past year.
8) Presence of hepatic or renal dysfunction. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
AUC0-last: The area under the analyte concentration versus time
curve, from time zero (0) to the time of the last measurable analyte
concentration, as calculated by the lin-up/log-down variant of the
trapezoidal method.
Cmax: Maximum measured analyte concentration over the sampling
period.
Tmax: Time of the maximum measured analyte concentration over the
sampling period. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
(0-hour) and 0.5, 1, 1.5, 2, 3, 4, 6, 12, 24, 48 and 72 hours post-dose |
|
E.5.2 | Secondary end point(s) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
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 |
Comparative Bioavailability |
|
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 |
Zontivity™ 2.08 mg tabletc |
|
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 |
|
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
|
Last study specific procedure in the last period of the study or the last
study specific procedure prior to the discontinuation of a subject from
the study. |
|
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |