Clinical Trials Register

Summary
EudraCT Number:	2013-000864-28
Sponsor's Protocol Code Number:	DAP-PEDOST-11-03
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-07-05
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

2013-000864-28

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blinded Comparative Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Daptomycin Versus Active Comparator in Pediatric Subjects With Acute Hematogenous Osteomyelitis Due to Gram-Positive Organisms

A.3.1

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

A study to evaluate the effectiveness, safety and the body's ability to absorb, distribute, metabolize and excrete Daptomycin compared to Vancomycin or nafcillin in children who suffer from infection of the bone or bone marrow due to bacteria

A.4.1

Sponsor's protocol code number

DAP-PEDOST-11-03

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01922011

A.5.4

Other Identifiers

Name:

Merck Sharp & Dohme Corp.

Number:

MK-3009-006

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	Cubist Pharmaceuticals, LLC
B.1.3.4	Country	Switzerland
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	Cubist Pharmaceuticals, LLC
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cubist Pharmaceuticals, LLC
B.5.2	Functional name of contact point	Mary Beth Dorr
B.5.3	Address:
B.5.3.1	Street Address	Weystrasse 20
B.5.3.2	Town/ city	Lucerne
B.5.3.3	Post code	6006
B.5.3.4	Country	Switzerland
B.5.6	E-mail	mary.beth.dorr@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	Cubicin®
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Ltd (previously from Novartis Europharm Limited)
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 injection/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	DAPTOMYCIN
D.3.9.1	CAS number	103060-53-3
D.3.9.4	EV Substance Code	SUB06910MIG
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	500
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	Vancomycin
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	VANCOMYCIN
D.3.9.1	CAS number	1404-90-6
D.3.9.4	EV Substance Code	SUB05076MIG
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: 3
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	Nafcillin (or β-lactam equivalent)
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 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	NAFCILLIN
D.3.9.1	CAS number	147-52-4
D.3.9.4	EV Substance Code	SUB09118MIG
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

Acute Hematogenous Osteomyelitis Due to Gram-Positive Organisms

E.1.1.1

Medical condition in easily understood language

Bacterial infection and inflammation of the bone or bone marrow

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10000959
E.1.2	Term	Acute osteomyelitis
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 demonstrate the noninferiority of daptomycin compared with vancomycin (or equivalent) or nafcillin (or ?-lactam equivalent) in pediatric subjects with AHO with respect to improvement in the general categories of Pain, Inflammation, and Limb Function on or before Study Day 5 in the MITT Analysis Set.

E.2.2

Secondary objectives of the trial

- To evaluate the efficacy of the Sponsor drug versus comparator in pediatric subjects with AHO
- To evaluate the safety and tolerability of daptomycin versus comparator in pediatric subjects with AHO
- To evaluate the pharmacokinetics of daptomycin in pediatric subjects with AHO

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Obtain Informed Consent;
2. Be 1 year to < 18 years old; a stepwise approach will be implemented to gate enrollment as follows: enrollment will begin with children aged 2-17 years; after an external Drug Safety Monitoring Board (DSMB) review, enrollment will be broadened to 1-17 years.
3. Have diagnosis of suspected or confirmed AHO warranting IV antibacterial therapy as inpatient, based on clinical, imaging and/or microbiological evidence as outlined below:
I. Clinical evidence of fever accompanied by symptoms on the affected limb that include but it is not limited to pain, tenderness on palpation, inflammation, warmth, swelling, difficulty bearing weight, motion restriction, loss of function
II. Radiologic imaging (magnetic resonance imaging [MRI], bone scan, x-ray, or computed tomography [CT] scan) consistent with osteomyelitis OR Microbiological evidence (gram stain, culture or polymerase chain reaction (PCR)) from a bone biopsy or bone aspirate (if available), or blood
III. Laboratory evidence: C-reactive protein (CRP) elevated, Erythrocyte sedimentation rate (ESR) elevated, leukocytosis or leukopenia, immature neutrophils
4. Confirmed (I, II, and III) OR suspected (I and III) that must be confirmed post-randomization

E.4

Principal exclusion criteria

1.Have documented history of any hypersensitivity or allergic reaction to daptomycin
2.Have septic arthritis only (without AHO)
3.Have acute hematogenous osteomyelitis that is located in the spine
4.Have chronic osteomyelitis (i.e. symptoms of osteomyelitis > 21 days) or osteomyelitis with complications requiring non-routine surgical treatment (i.e. sequestration).
5.Have major trauma, penetrating trauma (including a puncture wound of the foot), postoperative osteomyelitis, foreign body in or adjacent to affected bone or joint, or other iatrogenic bone or joint infections present at the site of infection
6.Have acute hematogenous osteomyelitis due to a proven gram-negative organism
7.Have transient tenosynovitis, juvenile rheumatoid arthritis (JRA), reactive arthritis, bony tumors, and other osteoarticular diseases suspected to be due to a nonbacterial (eg, fungal or mycobacterial) etiology
8.Receive more than 24 hours of effective intravenous antibacterial therapy for osteomyelitis within 96 hours before randomization unless microbiological or clinical failure is documented
9.Require any potentially effective concomitant systemic antibacterial therapy for gram-positive infections
10.Have history of seizures (except febrile seizure of childhood)
11.Have peripheral neuropathy
12.Have history of rhabdomyolysis (with the exception of muscle injury due to trauma)
13.Have Sickle cell anemia
14.Cannot be assessed clinically during the study
15.Have any condition (eg, cystic fibrosis, current septic shock) that would make the subject, in the opinion of the Investigator, unsuitable for the study
16.Have significant reduced creatinine clearance (CrCl) < 50 mL/min/1.73 m2
17.Have evidence of significant hepatic, hematologic, or immunologic dysfunction
18.Have Creatine kinase (CK) elevation ≥ 10 × ULN (upper limit of normal) without symptoms or ≥ 5 × ULN with symptoms
19.If female, must not be pregnant or nursing and if required by age and life style take appropriate measures to not get pregnant during the study.
20.Have participated in any study involving administration of an investigational agent or device or daptomycin within 30 days
21.Are unable or unwilling to adhere to the study-specified procedures and restrictions
22.Has suspected or confirmed pneumonia, empyema, meningitis, or endocarditis.

E.5 End points

E.5.1

Primary end point(s)

Percentage of Participants With Clinical Improvement in the 3 General Categories of Pain, Inflammation, and Limb Function Based on the Investigator's Overall Assessment of Severity of Each of the Symptom Categories.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to study Day 5

E.5.2

Secondary end point(s)

1. Percentage of Participants With Clinical Improvement Measured as a Composite End Point of Pain, Inflammation, Limb Function, Body Temperature, and C-reactive Protein at End-of IV (EOIV) Therapy Visit.
2. Percentage of Participants With a Favorable Clinical Outcome
3.Percentage of Participants With a Clinical Cure Categorized by Baseline Pathogen at Test of Cure
4. Percentage of Participants With Sustained Clinical Improvement
5.Percentage of Participants With a Favorable Microbiological Response Categorized by Baseline Pathogen at Test of Cure

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Up to study Day 5
2.to 5. Baseline (within 48 hours prior to first dose of IV study drug) - and up to Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77)

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

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Standard of care; vancomycin or nafcillin

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Argentina

Australia

Chile

Georgia

Israel

Malaysia

Panama

Peru

Russian Federation

South Africa

Ukraine

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

LSLV

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

Yes

F.1.1

Number of subjects for this age range:

149

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)

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.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

144

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 planned

G. Investigator Networks to be involved in the Trial

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

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