Clinical Trials Register

Summary
EudraCT Number:	2018-004704-19
Sponsor's Protocol Code Number:	MK-7625A-036
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-01-10
Trial 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

Greece - EOF

A.2

EudraCT number

2018-004704-19

A.3

Full title of the trial

A Phase 1, open-label, non-comparative, multicenter clinical study to evaluate the safety, tolerability, and pharmacokinetics of ceftolozane/tazobactam (MK-7625A) in pediatric participants with nosocomial pneumonia

A.3.1

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

Safety and pharmacokinetics of ceftolozane/tazobactam in pediatric participants with nosocomial pneumonia

A.4.1

Sponsor's protocol code number

MK-7625A-036

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/277/2017

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Merck Sharp & Dohme LLC, 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 LLC, 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	Merck Sharp & Dohme LLC, a subsidiary of Merck & Co.,Inc
B.5.2	Functional name of contact point	Matthew Girard Johnson
B.5.3	Address:
B.5.3.1	Street Address	126 East Lincoln Ave., P.O. Box 2000
B.5.3.2	Town/ city	Rahway, NJ
B.5.3.3	Post code	07065
B.5.3.4	Country	United States
B.5.4	Telephone number	+12673053540
B.5.5	Fax number	+12673056545
B.5.6	E-mail	matthew.johnson1@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	Yes
D.2.1.1.1	Trade name	Zerbaxa
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Powder for solution for infusion
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	Ceftolozane
D.3.9.1	CAS number	936111-69-2
D.3.9.2	Current sponsor code	MK7625A
D.3.9.3	Other descriptive name	CEFTOLOZANE SULFATE
D.3.9.4	EV Substance Code	SUB167761
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tazobactam
D.3.9.1	CAS number	89785-84-2
D.3.9.2	Current sponsor code	MK7625A
D.3.9.3	Other descriptive name	TAZOBACTAM SODIUM
D.3.9.4	EV Substance Code	SUB04682MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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

Nosocomial pneumonia

E.1.1.1

Medical condition in easily understood language

Nosocomial pneumonia

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10052596
E.1.2	Term	Nosocomial pneumonia
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 safety and tolerability of ceftolozane/tazobactam for all participants

E.2.2

Secondary objectives of the trial

To evaluate the pharmacokinetics (PK) of multiple doses of ceftolozane/tazobactam for each age group and/or dose level

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Has a diagnosis of proven or suspected NP (including HABP or VABP), as determined by the investigator.
Note: The diagnosis of NP does not require a pathogen to be isolated from a diagnostic test.
2. Is hospitalized and anticipated to receive a minimum of 8 days of concomitant standard-of-care antibiotic therapy for proven or suspected NP. The concomitant standard-of-care antibiotic therapy can have coverage for either gram positive and/or gram-negative respiratory pathogen(s).
Note: Concomitant SOC antibiotics may be stopped before the 8-day minimum at the discretion of the investigator. Participants who discontinue or complete concomitant SOC antibiotic therapy in less than 8 days may also discontinue ceftolozane/tazobactam prior to the minimum duration of 8 days at the investigator’s discretion. However, participants are strongly encouraged to receive a minimum of 8 days of ceftolozane/tazobactam.
Demographics:
3. Is male or female (not pregnant or nursing) from birth (defined as >32 weeks gestational age and ≥7 days postnatal) to <18 years of age inclusive, at the time of signing the informed consent/assent.
Male Participants:
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of study intervention:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause ) as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
Female Participants:
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least [30 days] after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within [48 hours] before the first dose of study intervention.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent/Assent:
4. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study.
Additional Categories:
5. Is able to comply with all study procedures and restrictions for the duration of the study.

E.4

Principal exclusion criteria

Medical Conditions:
1. Has a documented history of any moderate or severe hypersensitivity (or allergic) reaction to any β-lactam antibacterial.
Note: A history of a rash while on a β-lactam antibiotic does not automatically exclude a participant (eg, a participant with history of a mild rash followed by uneventful re-exposure may be considered for enrollment).
2. For Groups 1-4, has moderate to severe impairment of renal function, defined as an estimated (CrCL) <50 mL/min/1.73 m2 based on the revised Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
For Group 5, has CrCL <20 mL/min/1.73 m2 based on the revised Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
Prior/Concomitant Therapy
3. Is receiving or is anticipated to receive piperacillin/tazobactam while receiving ceftolozane/tazobactam or has received piperacillin/tazobactam within 24 hours prior to the first dose of ceftolozane/tazobactam.
Prior/Concurrent Clinical Study Experience
4. Participation in any clinical study of a therapeutic investigational product within 30 days prior to the first dose of ceftolozane/tazobactam.
5.Previous participation in any study of ceftolozane or ceftolozane/tazobactam.
Diagnostic Assessments:
Not applicable.
Other Exclusions:
6. Has one or more of the following laboratory abnormalities in a specimen obtained at screening:
• Absolute neutrophil count (ANC) <1000/mm3
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × the upper limit of normal (ULN)
• Total bilirubin ≥2 × the ULN (if 7 to ≤28 days of age and breastfeeding, total bilirubin >10 mg/dL OR ≥2 × ULN).
7. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the participant or the quality of study data.
8. Has any rapidly progressing disease or immediately life-threatening illness including acute hepatic failure or septic shock.
9. Has active immunosuppression, including any of the following:
•human immunodeficiency virus (HIV) infection, with a known CD4 percentage of <15% in pediatric participants ≤5 years of age, or CD4 count of <200 cells/mm3 in pediatric participants >5 years of age
•active hematological malignancy
•recipient of solid organ or bone marrow transplants
•currently on immunosuppressive therapy, including cancer chemotherapy currently on medications for prevention of transplant rejection
•chronic administration of systemic corticosteroids (defined as the systemic equivalent of ≥2 mg/kg total daily dose of prednisone for participants ≤20 kg, or >40 mg of prednisone per day for participants >20 kg, administered continuously for more than 14 days in the 30 days prior to the first dose of
ceftolozane/tazobactam)
10. Is or has an immediate family member (eg, parent/legal guardian or sibling) who is investigational site or Sponsor staff directly involved with this study.

E.5 End points

E.5.1

Primary end point(s)

1.Percentage of participants with any adverse events (AEs)
2.Percentage of participants with any serious AEs (SAEs)
3.Percentage of participants with any drug-related AEs
4.Percentage of participants with any drug-related SAEs
5.Percentage of participants with AEs leading to discontinuation of study intervention

E.5.1.1

Timepoint(s) of evaluation of this end point

1.Up to Day 31
2.Up to Day 31
3.Up to Day 31
4.Up to Day 31
5.Up to Day 14

E.5.2

Secondary end point(s)

1.Plasma concentrations of ceftolozane
2.Plasma concentrations of tazobactam
3.Area under the concentration-time curve of an 8-hour dosing interval (AUC0-8) of plasma ceftolozane
4.Area under the concentration-time curve of an 8-hour dosing interval (AUC0-8) of plasma tazobactam
5.Maximum observed concentration during a dosage interval (Cmax) of plasma ceftolozane
6.Maximum observed concentration during a dosage interval (Cmax) of plasma tazobactam
7.Elimination half-life (t1/2) of plasma ceftolozane
8.Elimination half-life (t1/2) of plasma tazobactam
9.Volume of distribution (Vd) of plasma ceftolozane
10.Volume of distribution (Vd) of plasma tazobactam
11.Clearance (CL) of plasma ceftolozane
12.Clearance (CL) of plasma tazobactam

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 3: 1, between 4-5, and between 7-8 hours after start of infusion

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

Yes

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

Evaluate the safety, tolerability and the PK in pediatric participants

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

E.8.1.1

Randomised

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

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

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

United States

Russian Federation

Ukraine

Estonia

Greece

Spain

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

LDA

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

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

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

Yes

F.1.1.2.1

Number of subjects for this age range:

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

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

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

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)

None

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-04-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-14

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
Orphan Designation Number:
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