Clinical Trials Register

Summary
EudraCT Number:	2014-004350-34
Sponsor's Protocol Code Number:	MK-5348-040
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2014-10-29
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2014-004350-34

A.3

Full title of the trial

A Comparative Bioavailability Study of a Tablet versus an Investigational
Oral Suspension of Vorapaxar

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Comparison of Pediatric Formulation (liquid) to Adult Formulation
(tablets)

A.3.2

Name or abbreviated title of the trial where available

PK of Pediatric Formulation

A.4.1

Sponsor's protocol code number

MK-5348-040

A.5.4

Other Identifiers

Name:

CRO number

Number:

2014-3621

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/222/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.,Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merck Sharp & Dohme Corp.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck Sharp & Dohme Corp.
B.5.2	Functional name of contact point	Clinical Monitor
B.5.3	Address:
B.5.3.1	Street Address	351 North Sumneytown Pike
B.5.3.2	Town/ city	North Wales, PA
B.5.3.3	Post code	19454
B.5.3.4	Country	United States
B.5.6	E-mail	martin_behm@merck.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Vorapaxar
D.3.2	Product code	MK-5348
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VORAPAXAR
D.3.9.3	Other descriptive name	VORAPAXAR SULPHATE
D.3.9.4	EV Substance Code	SUB119537
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.2085
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Zontivity
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SHARP & DOHME
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Zontivity™
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VORAPAXAR
D.3.9.3	Other descriptive name	VORAPAXAR SULPHATE
D.3.9.4	EV Substance Code	SUB119537
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.08
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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

Blood clots

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

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

Not applicable

E.2.3

Trial contains a sub-study

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)

not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

not applicable

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Comparative Bioavailability

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

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

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?

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

Canada

E.8.7

Trial has a data monitoring committee

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not applicable

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Pharma Medica Research Inc.
G.4.3.4	Network Country	Canada

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	Canada

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