Clinical Trials Register

Summary
EudraCT Number:	2013-003831-31
Sponsor's Protocol Code Number:	8228-001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-03-04
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
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-003831-31

A.3

Full title of the trial

A Phase III Randomized, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of MK-8228 (Letermovir) for the Prevention of Clinically Significant Human Cytomegalovirus (CMV) Infection in Adult, CMV-Seropositive Allogeneic Hematopoietic Stem Cell Transplant Recipients

A.3.1

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

MK-8228 vs. Placebo in Prevention of CMV infection in HSCT Recipients

A.3.2

Name or abbreviated title of the trial where available

MK-8228 vs. Placebo in Prevention of CMV infection in HSCT Recipients

A.4.1

Sponsor's protocol code number

8228-001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

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., a subsidiary of Merck & Co., Inc.
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	MSD Italia S.r.l.
B.5.2	Functional name of contact point	Divisione Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	Via Fratelli Cervi, snc – Centro Direzionale Milano Due – Palazzo Canova
B.5.3.2	Town/ city	Segrate (MI)
B.5.3.3	Post code	20090
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390221018402
B.5.5	Fax number	+390221018629
B.5.6	E-mail	gcto.italy@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	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/849
D.3 Description of the IMP
D.3.1	Product name	Letermovir
D.3.2	Product code	MK-8228
D.3.4	Pharmaceutical form	Film-coated 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	Letermovir
D.3.9.1	CAS number	917389-32-3
D.3.9.2	Current sponsor code	MK-8228
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	240
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	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	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/849
D.3 Description of the IMP
D.3.1	Product name	Letermovir
D.3.2	Product code	MK-8228
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Letermovir
D.3.9.1	CAS number	917389-32-3
D.3.9.2	Current sponsor code	MK-8228
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	240
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Clinically significant CMV infection

E.1.1.1

Medical condition in easily understood language

Clinically significant CMV infection

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10009703
E.1.2	Term	CMV infection
E.1.2	System Organ Class	100000004862

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 efficacy of MK-8228 in the prevention of clinically significant CMV infection through Week 24 (~6 months) post-transplant following administration of MK-8228 or placebo.

E.2.2

Secondary objectives of the trial

1) To evaluate the safety and tolerability of MK-8228.
2) To evaluate the efficacy of MK-8228 in the prevention of clinically significant CMV infection through Week 14 (~100 days) post-transplant.
3) To evaluate the efficacy of MK-8228 as assessed by time to onset of clinically significant CMV infection through Week 24 (~6 months) post-transplant.
4) To determine the incidence of CMV disease through Week 14 post -transplant and Week 24 post-transplant.
5) To assess the incidence of PET for CMV viremia through Week 14 post-transplant and Week 24 post-transplant.
6) To assess the time to initiation of PET for CMV viremia through Week 14 post-transplant and Week 24 post-transplant.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.

E.3

Principal inclusion criteria

1. be ≥ 18 years of age on the day of signing informed consent.
2. have documented seropositivity for CMV (recipient CMV IgG seropositivity [R+]) within 1 year before HSCT.
3. be receiving a first allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant).
4. have undetectable CMV DNA (as confirmed by the central laboratory) from a plasma sample collected within 5 days prior to randomization.
5. be within 28 days post-HSCT at the time of randomization.
6. be highly unlikely to become pregnant or to impregnate a partner

E.4

Principal exclusion criteria

1. received a previous allogeneic HSCT
2. has a history of CMV end-organ disease within 6 months prior to randomization.
3. has evidence of CMV viremia from a central or local laboratory at any time prior to randomization.
4. received within 7 days prior to screening or plans to receive during the study any of the following: ganciclovir; valganciclovir; foscarnet; acyclovir (at doses > 3200 mg PO per day or > 25 mg/kg IV per day); valacyclovir (at doses > 3000 mg PO per day); famciclovir (at doses > 1500 mg PO per day)
5. received within 30 days prior to screening or plans to receive during the study any of the following: cidofovir; CMV hyper-immune globulin; Any investigational CMV antiviral agent/biologic therapy
6. has suspected or known hypersensitivity to active or inactive ingredients of
letermovir formulations.
7. has severe hepatic insufficiency (defined as Child-Pugh Class C; see Appendix 12.5).
8. has serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x the upper limit of normal (ULN) or serum total bilirubin > 2.5 x ULN.
9. has end-stage renal impairment with a creatinine clearance less than 10 mL/min, as calculated by the Cockcroft-Gault equation using serum creatinine.
10. has both moderate hepatic insufficiency AND moderate renal insufficiency.
11. has an uncontrolled infection on the day of randomization.
12. requires mechanical ventilation or is hemodynamically unstable at the time of rndomization.
13. has documented positive results for human immunodeficiency virus antibody (HIVAb), hepatitis C virus antibody (HCV-Ab) with detectable HCV RNA, or hepatitis B
surface antigen (HBsAg) within 90 days prior to randomization.
14. has active solid tumor malignancies with the exception of localized basal cell or
squamous cell skin cancer or the condition under treatment (e.g., lymphomas).
15. is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 90 days after the last dose of study therapy.
16. is expecting to donate eggs or sperm starting from the time of consent through 90 days after the last dose of study therapy.
17. is currently participating or has participated in a study with an unapproved investigational compound or device within 28 days, or 5X half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of
initial dosing on this study. Subjects previously treated with a monoclonal antibody
will be eligible to participate after a 28-day washout period.
18. has previously participated in this study or any other study involving MK-8228
(letermovir).
19. has previously participated or is currently participating in any study involving
administration of a CMV vaccine or another CMV investigational agent, or is
planning to participate in a study of a CMV vaccine or another CMV investigational
agent during the course of this study.
20. is or has an immediate family member (spouse or children) who is investigational site or Sponsor staff directly involved with this trial.
21. is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence.
22. has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or would be put at undue risk as judged by the investigator, such that it is not in the best interest of the subject to participate in this study.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint of the study is the proportion of subjects with clinically significant CMV infection through Week 24 (~6 months) post-transplant, defined as the occurrence of either one of the following outcomes:
•onset of CMV end-organ disease
OR
•initiation of anti-CMV PET based on documented CMV viremia (as measured by the central laboratory) and the clinical condition of the subject. Initiation of PET in this study refers to the practice of initiating therapy with the following approved anti-CMV agents when active CMV viral replication is documented: ganciclovir, valganciclovir, foscarnet, and/or cidofovir.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24 (~6 months) post- HSCT transplant

E.5.2

Secondary end point(s)

1. Proportion of subjects with clinically significant CMV infection through Week 14 (~100 days) post-transplant
2. Time to onset of clinically significant CMV infection through Week 24 (~6 months) post-transplant
3. Proportion of subjects with CMV disease through Week 14 post-transplant and Week 24 post-transplant
4. Proportion of subjects with initiation of PET for documented CMV viremia through Week 14 post-transplant and Week 24 post-transplant.
5. The time to initiation of PET for documented CMV viremia through Week 24 post-transplant.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 14, Week 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

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)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Belgium

Canada

France

Italy

Japan

Austria

New Zealand

Romania

Sweden

Australia

Brazil

Finland

Germany

Korea, Republic of

Lithuania

Spain

Peru

Poland

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

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:

270

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

270

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

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.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

280

F.4.2.2

In the whole clinical trial

540

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)

Subjects will receive local standard of care

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	European Group for Blood and Marrow Transplantation
G.4.3.4	Network Country	Spain

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-05-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-03-19

P. End of Trial
P.	End of Trial Status	Completed

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