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Clinical Trial Results:
Comparison of teicoplanin and vancomycin in terms of efficacy and side effect profile during initial antibiotic treatment of febrile neutropenic patients at high risk for gram-positive infection: multi-center, prospective, randomized study

Summary
EudraCT number	2014-004628-23
Trial protocol	Outside EU/EEA
Global end of trial date	09 Aug 2007

Results information
Results version number	v1(current)
This version publication date	27 Apr 2016
First version publication date	05 Aug 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

M000507_6004

ISRCTN number

US NCT number

NCT00454272

WHO universal trial number (UTN)

Sponsor organisation name

Sanofi-aventis İlaçları Ltd Şti

Sponsor organisation address

Büyükdere Cad No:193 K: 3-10, Levent Istanbul, Turkey, 34394

Public contact

Trial Transparency Team, Sanofi Aventis Recherche & Developpement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi Aventis Recherche & Developpement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

04 Jun 2008

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Aug 2007

Was the trial ended prematurely?

Main objective of the trial

To evaluate whether or not the use of Teicoplanin containing regimen during initial empirical antibiotic treatment of febrile neutropenic subjects at high risk for gram-positive infection was at least equivalent to Vancomycin containing regimen in terms of fever remission or eradication of isolated gram-positive bacteria. To evaluate whether or not there was any difference between the two regimens in terms of side effect profiles.

Protection of trial subjects

Paediatric subjects: The study was conducted by investigators experienced in the treatment of pediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort. Adult subjects: Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Subjects received Amikacin and Ceftazidime throughout the study.

Evidence for comparator

Actual start date of recruitment

18 Jan 2005

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Turkey: 190

Worldwide total number of subjects

190

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

138

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 21 sites in Turkey. A total of 190 subjects were enrolled between 18 January 2005 and 3 August 2007.

Screening details

A total of 190 subjects were randomized and treated

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Teicoplanin

Arm description

Ceftazidime + Amikacin + Teicoplanin with treatments duration minimum 5 days maximum 21 days.

Arm type

Experimental

Investigational medicinal product name

Teicoplanin

Investigational medicinal product code

M000507

Other name

Targocid

Pharmaceutical forms

Concentrate and solvent for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Adult (400 mg) and Children aged 2-16 years (10 mg/kg): Loading dose every 12 hours for first 3 doses then maintenance dose once daily.

Vancomycin

Arm description

Ceftazidime + Amikacin + Vancomycin with treatments duration minimum 5 days maximum 21 days.

Arm type

Active comparator

Investigational medicinal product name

Vancomycin

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Children over 2 years of age: 10 mg/kg every 6 hours. Adults: 1 gr. every 12 hours.

Number of subjects in period 1	Teicoplanin	Vancomycin
Started	97	93
Treated	97	93
Completed	89	88
Not completed	8	5
Death	7	4
Lost to follow-up	1	1

Baseline characteristics

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Reporting group title

Teicoplanin

Reporting group description

Ceftazidime + Amikacin + Teicoplanin with treatments duration minimum 5 days maximum 21 days.

Reporting group title

Vancomycin

Reporting group description

Ceftazidime + Amikacin + Vancomycin with treatments duration minimum 5 days maximum 21 days.

Reporting group values	Teicoplanin	Vancomycin	Total
Number of subjects	97	93	190
Age categorical
Units: Subjects
Children (2-11 years)	12	11	23
Adolescents (12-17 years)	8	6	14
Adults (18-64 years)	69	69	138
From 65-84 years	8	7	15
Gender categorical
Units: Subjects
Female	42	42	84
Male	55	51	106
Diagnosis
Units: Subjects
Hematologic Malignity	86	80	166
Solid Tumor	6	3	9
Not Available	5	10	15

End points

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Reporting group title

Teicoplanin

Reporting group description

Ceftazidime + Amikacin + Teicoplanin with treatments duration minimum 5 days maximum 21 days.

Reporting group title

Vancomycin

Reporting group description

Ceftazidime + Amikacin + Vancomycin with treatments duration minimum 5 days maximum 21 days.

Primary: Number of Subjects According to The Treatment Response

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End point title

Number of Subjects According to The Treatment Response

End point description

Success: Remission of all pre-treatment symptoms and signs without need for additional antibiotics, eradication of etiological microorganisms, no recurrence of symptoms for at least 5 days after completion of treatment and inability to isolate etiological microorganisms. Failure: Addition of another antibacterial treatment, resistance to study drug or infection-associated death of the subject. Analysis was performed on intent-to-treat (ITT) population defined as all subjects who had satisfied the inclusion criteria and been randomized for the study. Number of subjects analyzed = subjects with data available at specified time points.

End point type

Primary

End point timeframe

5 days after the completion of treatment maximum of 26 days

End point values	Teicoplanin	Vancomycin
Number of subjects analysed	97	90
Units: subjects
Successful	54	48
Unsuccessful	18	22
Successful with modification	21	16
Not evaluated	4	4

Teicoplanin vs Vancomycin

Comparison groups

Teicoplanin v Vancomycin

Number of subjects included in analysis

187

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.761

Method

Chi-squared

Confidence interval

Secondary: Percentage of Subjects With New Infection

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End point title

Percentage of Subjects With New Infection

End point description

Presence of a new infection under treatment or 5 days after the treatment. Analysis was performed on ITT population. Number of subjects analyzed = subjects with data available at specified time points.

End point type

Secondary

End point timeframe

At the end of treatment maximum 21 days

End point values	Teicoplanin	Vancomycin
Number of subjects analysed	93	88
Units: percentage of subjects
number (not applicable)	22.6	21.6

No statistical analyses for this end point

Secondary: Percentage of Subjects With Protocol Treatment Modification or Alteration

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End point title

Percentage of Subjects With Protocol Treatment Modification or Alteration

End point description

Analysis was performed on ITT population. Number of subjects analyzed = subjects with data available at specified time points.

End point type

Secondary

End point timeframe

At the end of treatment maximum 21 days

End point values	Teicoplanin	Vancomycin
Number of subjects analysed	93	89
Units: percentage of subjects
number (not applicable)
Addition of new drug	34.4	31.8
Cessation of protocol drug and start of new drug	29.3	30.6

No statistical analyses for this end point

Secondary: Survival at 30 Days

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End point title

Survival at 30 Days

End point description

Kaplan Meier test was used for survival analyses. Analysis was performed on ITT population. Number of subjects analyzed = subjects with data available at specified time points.

End point type

Secondary

End point timeframe

30 days

End point values	Teicoplanin	Vancomycin
Number of subjects analysed	94	81
Units: percentage of subjects
number (not applicable)
Survival (Non-infection)	84	84
Survival (Infection)	7.4	7.4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Day 21) regardless of seriousness or relationship to investigational product

Adverse event reporting additional description

Reported adverse events and deaths are Adverse Events that developed/worsened and deaths that occurred during the time of 1st administration of study drug until discharge.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Teicoplanin

Reporting group description

Ceftazidime + Amikacin + Teicoplanin with treatments duration minimum 5 days maximum 21 days.

Reporting group title

Vancomycin

Reporting group description

Ceftazidime + Amikacin + Vancomycin with treatments duration minimum 5 days maximum 21 days.

Serious adverse events	Teicoplanin	Vancomycin
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 97 (8.25%)	9 / 93 (9.68%)
number of deaths (all causes)	7	4
number of deaths resulting from adverse events
Investigations
Activated partial thromboplastin time
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic neoplasm
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Vascular disorders
Cerebral hematoma
subjects affected / exposed	0 / 97 (0.00%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
bleeding
subjects affected / exposed	0 / 97 (0.00%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Haemorrhage
subjects affected / exposed	3 / 97 (3.09%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	2 / 3	0 / 0
Blood and lymphatic system disorders
Coagulopathy
subjects affected / exposed	2 / 97 (2.06%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 97 (0.00%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Vomiting
subjects affected / exposed	0 / 97 (0.00%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 97 (0.00%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 97 (1.03%)	2 / 93 (2.15%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Nephropathy toxic
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anuria
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Aspergillus infection
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
bacterial sepsis
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Infection
subjects affected / exposed	3 / 97 (3.09%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	1 / 3	0 / 1
Sepsis
subjects affected / exposed	1 / 97 (1.03%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
septic schock
subjects affected / exposed	1 / 97 (1.03%)	0 / 93 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	1 / 97 (1.03%)	1 / 93 (1.08%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Teicoplanin	Vancomycin
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 97 (16.49%)	16 / 93 (17.20%)
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	5 / 97 (5.15%)	5 / 93 (5.38%)
occurrences all number	5	5
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	5 / 97 (5.15%)	5 / 93 (5.38%)
occurrences all number	5	5
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	10 / 97 (10.31%)	9 / 93 (9.68%)
occurrences all number	11	10

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
Comparison of teicoplanin and vancomycin in terms of efficacy and side effect profile during initial antibiotic treatment of febrile neutropenic patients at high risk for gram-positive infection: multi-center, prospective, randomized study

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects According to The Treatment Response

Primary: Number of Subjects According to The Treatment Response

Secondary: Percentage of Subjects With New Infection

Secondary: Percentage of Subjects With New Infection

Secondary: Percentage of Subjects With Protocol Treatment Modification or Alteration

Secondary: Percentage of Subjects With Protocol Treatment Modification or Alteration

Secondary: Survival at 30 Days

Secondary: Survival at 30 Days

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: Comparison of teicoplanin and vancomycin in terms of efficacy and side effect profile during initial antibiotic treatment of febrile neutropenic patients at high risk for gram-positive infection: multi-center, prospective, randomized study

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects According to The Treatment Response

Primary: Number of Subjects According to The Treatment Response

Secondary: Percentage of Subjects With New Infection

Secondary: Percentage of Subjects With New Infection

Secondary: Percentage of Subjects With Protocol Treatment Modification or Alteration

Secondary: Percentage of Subjects With Protocol Treatment Modification or Alteration

Secondary: Survival at 30 Days

Secondary: Survival at 30 Days

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Comparison of teicoplanin and vancomycin in terms of efficacy and side effect profile during initial antibiotic treatment of febrile neutropenic patients at high risk for gram-positive infection: multi-center, prospective, randomized study