Clinical Trial Results:
A Phase III, Observer-blind, randomized, controlled, multi-center study to inventigate the immunogenicity and safety of the Vaxem Hib™ in 2-4 months old healthy infants in China, according to the recommended regimen of 3 intramascular doses given one month apart.

Due to a system error, the data reported in v1 is not correct and has been removed from public view.

Summary
EudraCT number	2014-005159-24
Trial protocol	Outside EU/EEA
Global end of trial date	15 Feb 2009

Results information
Results version number	v2(current)
This version publication date	26 May 2016
First version publication date	10 Jun 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set re-QC study because of EudraCT system glitch and updates to results are required.

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

M37P2

ISRCTN number

US NCT number

NCT00808392

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Vaccines & Diagnostics

Sponsor organisation address

via Fiorentina 1, Siena, Italy, 53100

Public contact

Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.com

Scientific contact

Posting Director, Novartis Vaccines, RegistryContactVaccinesUS@novartis.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

21 May 2009

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Feb 2009

Was the trial ended prematurely?

Main objective of the trial

Primary study objective: To demonstrate that Vaxem Hib given to healthy infants aged 2 - 4 months at study entry is non-inferior to comparator vaccine HIBERIX (GlaxoSmithKline) with regard to percentage of subjects with antibody levels of ≥ 0.15 micrograms/mL one month after last vaccination dose as measured by anti-PRP ELISA.

Protection of trial subjects

This clinical trial was carried out in accordance with relative requirements of Provisions for Drug Registration and World Health Organization (WHO) Guidelines for Good Clinical Practice (GCP) and Guidelines on Clinical Evaluation of Vaccines issued by State Food and Drug Administration and under the principle of Helsinki Declaration. Study vaccines were not administered to individuals with known hypersensitivity to any component of the vaccines. An oral temperature ≥38.0°C (≥100.4°F) or serious active infection was a reason for delaying vaccination. Standard vaccination practices were observed and care was taken to administer the injection intramuscularly. As with all injectable vaccines, appropriate medical treatment and supervision was readily available in case of rare anaphylactic reactions following administration of the study vaccine. Epinephrine 1:1000 and diphenhydramine was available in case of any anaphylactic reactions. Care was taken to ensure that the vaccine was not injected into a blood vessel.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Oct 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

China: 916

Worldwide total number of subjects

916

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)

916

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were enrolled at two sites in China.

Screening details

All subjects enrolled were included in the trial.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The trial was designed as an observer-blind study.

Are arms mutually exclusive

Yes

Vaxem Hib

Arm description

2-4 month old infants administered with 3 doses of Novartis Vaxem Hib™, each dose given one month apart.

Arm type

Experimental

Investigational medicinal product name

CRM197 conjugate Haemophilus influenzae type b conjugate vaccine

Investigational medicinal product code

Other name

Vaxem Hib

Pharmaceutical forms

Suspension for injection in pre-filled syringe

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of three 0.5 mL doses of Vaxem Hib™, vaccine administered IM into the deltoid muscle.

Hiberix

Arm description

2-4 month old infants administered with 3 doses of GSK HIBERIX® each dose given one month apart.

Arm type

Active comparator

Investigational medicinal product name

Tetanus Toxoid conjugate Haemophilus influenzae type b (Hib) vaccine

Investigational medicinal product code

Other name

Hiberix

Pharmaceutical forms

Powder for injection

Routes of administration

Intramuscular use

Dosage and administration details

Vaccination consisted of three 0.5 mL doses of GSK HIBERIX® vaccine administered IM into the deltoid muscle.

Number of subjects in period 1	Vaxem Hib	Hiberix
Started	611	305
Completed	576	289
Not completed	35	16
Adverse event, non-fatal	5	1
Lost to follow-up	2	-
Required by their parents	28	14
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Vaxem Hib

Reporting group description

2-4 month old infants administered with 3 doses of Novartis Vaxem Hib™, each dose given one month apart.

Reporting group title

Hiberix

Reporting group description

2-4 month old infants administered with 3 doses of GSK HIBERIX® each dose given one month apart.

Reporting group values	Vaxem Hib	Hiberix	Total
Number of subjects	611	305	916
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	611	305	916
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Subjects	0	0	0
Age continuous
Units: months
arithmetic mean (standard deviation)	3.1 ± 0.8	3.1 ± 0.8	-
Gender categorical
Units: Subjects
Female	298	147	445
Male	313	158	471

Subject analysis set title

All enrolled population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who had data in the DEMOG panel.

Subject analysis set title

All exposed population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who received study vaccination.

Subject analysis set title

Full analysis set (FAS, Immunogenicity)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who have received a study vaccination, and provide at least one evaluable serum sample

Subject analysis set title

Per Protocol Set (PPS, Immunogenicity)

Subject analysis set type

Per protocol

Subject analysis set description

All subjects have received all the relevant doses of vaccine correctly, and provide evaluable serum samples at the relevant time points, and have no major protocol violation as defined prior to unblinding

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who provide post-baseline safety data

Subject analysis sets values	All enrolled population	All exposed population	Full analysis set (FAS, Immunogenicity)	Per Protocol Set (PPS, Immunogenicity)	Safety set
Number of subjects	916	916	231	212	916
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	916	916	231	212	916
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	0	0	0	0	0
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Subjects	0	0	0	0	0
Age continuous
Units: months
arithmetic mean (standard deviation)	±	±	±	±	±
Gender categorical
Units: Subjects
Female
Male

End points

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Reporting group title

Vaxem Hib

Reporting group description

2-4 month old infants administered with 3 doses of Novartis Vaxem Hib™, each dose given one month apart.

Reporting group title

Hiberix

Reporting group description

2-4 month old infants administered with 3 doses of GSK HIBERIX® each dose given one month apart.

Subject analysis set title

All enrolled population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who had data in the DEMOG panel.

Subject analysis set title

All exposed population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects who received study vaccination.

Subject analysis set title

Full analysis set (FAS, Immunogenicity)

Subject analysis set type

Full analysis

Subject analysis set description

All subjects who have received a study vaccination, and provide at least one evaluable serum sample

Subject analysis set title

Per Protocol Set (PPS, Immunogenicity)

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Safety set

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who provide post-baseline safety data

Primary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 0.15 μg/mL at day 90

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End point title

Percentage of subjects with the serum anti-PRP antibody titers ≥ 0.15 μg/mL at day 90

End point description

Immunogenicity was measured as the percentage of subjects with seroconversion rate of anti-PRP antibody levels ≥0.15 μg/mL one month after the third vaccination.

End point type

Primary

End point timeframe

One month after third vaccination (Day 90)

End point values	Vaxem Hib	Hiberix
Number of subjects analysed	139	73
Units: Percentage of subjects
number (not applicable)
≥ 0.15 μg/mL	100	100
<0.15 g/mL	0	0

Non-inferiority of Vaxem Hib vs Hiberix

Statistical analysis description

The non-inferiority was statistically confirmed by inspection of the proportions of subjects with anti-PRP ELISA results≥0.15 μg/mL one month after last vaccination.

Comparison groups

Vaxem Hib v Hiberix

Number of subjects included in analysis

212

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Chi-squared

Parameter type

Rate difference

Point estimate

Confidence interval

level

95%

sides

1-sided

lower limit

upper limit

Secondary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 1.0 μg/mL at day 90

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End point title

Percentage of subjects with the serum anti-PRP antibody titers ≥ 1.0 μg/mL at day 90

End point description

Immunogenicity was measured as the percentage of subjects with long-term serum protection rate of anti-PRP antibody levels ≥ 1.0 μg/mL one month after the third vaccination in PPS.

End point type

Secondary

End point timeframe

One month after third vaccination (Day 90)

End point values	Vaxem Hib	Hiberix
Number of subjects analysed	139	73
Units: Percentage of subjects
number (not applicable)
≥ 1.0 μg/mL	99.3	97.3
<1.0 g/mL	0.7	2.7

Non-inferiority of Vaxem Hib vs Hiberix

Statistical analysis description

The non-inferiority was statistically confirmed by inspection of the proportions of subjects with anti-PRP ELISA results ≥ 0.15 μg/mL one month after last vaccination.

Comparison groups

Vaxem Hib v Hiberix

Number of subjects included in analysis

212

Analysis specification

Pre-specified

Analysis type

non-inferiority

Method

Chi-squared

Parameter type

Rate difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.98

upper limit

6.02

Secondary: Geometric mean of anti-PRP antibody concentrations of Vaxem Hib and Hiberix groups at day 90

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End point title

Geometric mean of anti-PRP antibody concentrations of Vaxem Hib and Hiberix groups at day 90

End point description

Immunogenecity was measured in terms of Geometric mean concentration with seroconversion rate of anti-PRP antibody levels (μg/mL) one month after the third vaccination in PPS.

End point type

Secondary

End point timeframe

One month after third vaccination (Day 90)

End point values	Vaxem Hib	Hiberix
Number of subjects analysed	139	73
Units: Percentage of subjects
geometric mean (confidence interval 95%)
μg/mL	60.56 (48.57 to 75.5)	35.62 (25.08 to 50.6)

No statistical analyses for this end point

Secondary: Number of Subjects Who Reported Local and Systemic Reactions After Each Vaccination of Vaxem Hib Vaccine or Hiberix vaccine.

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End point title

Number of Subjects Who Reported Local and Systemic Reactions After Each Vaccination of Vaxem Hib Vaccine or Hiberix vaccine.

End point description

Safety was assessed as the number of subjects who reported local and systemic reactions in the first 7 days after each of the 3 vaccinations withVaxem Hib Vaccine or Hiberix vaccine administered at day 0, day 30 and day 60 in safety population.

End point type

Secondary

End point timeframe

Day 0 through day 6 after each vaccination

End point values	Vaxem Hib	Hiberix
Number of subjects analysed	611	305
Units: Number of subjects
Tenderness – Vaccination 1	4	0
Tenderness – Vaccination 2	5	2
Tenderness – Vaccination 3	8	0
Erythema - Vaccination 1	3	2
Erythema - Vaccination 2	3	3
Erythema - Vaccination 3	8	1
Induration - Vaccination 1	8	1
Induration - Vaccination 2	5	0
Induration - Vaccination 3	5	1
Change in eating habits - Vaccination 1	2	5
Change in eating habits - Vaccination 2	4	0
Change in eating habits - Vaccination 3	2	0
Sleepiness - Vaccination 1	9	6
Sleepiness - Vaccination 2	4	3
Sleepiness - Vaccination 3	3	2
Unusual crying - Vaccination 1	13	11
Unusual crying - Vaccination 2	9	5
Unusual crying - Vaccination 3	4	0
Irritability - Vaccination 1	4	2
Irritability - Vaccination 2	0	0
Irritability - Vaccination 3	1	0
Rash - Vaccination 1	5	3
Rash - Vaccination 2	0	1
Rash - Vaccination 3	1	0
Fever (≥38 °C) - Vaccination 1	6	6
Fever (≥38 °C) - Vaccination 2	15	6
Fever (≥38 °C) - Vaccination 3	14	1
Analg/Antipyr medications used - Vaccination 1	8	6
Analg/Antipyr medications used - Vaccination 2	12	5
Analg/Antipyr medications used - Vaccination 3	15	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Throughout the study period (Day 0 to one month after third vaccination)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Vaxem Hib

Reporting group description

2-4 month old infants administered with 3 doses of Novartis Vaxem Hib™, each dose given one month apart.

Reporting group title

Hiberix

Reporting group description

2-4 month old infants administered with 3 doses of GSK HIBERIX® each dose given one month apart.

Serious adverse events	Vaxem Hib	Hiberix
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 611 (0.98%)	2 / 305 (0.66%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Injury, poisoning and procedural complications
Thermal burn
subjects affected / exposed	1 / 611 (0.16%)	0 / 305 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Intussusception
subjects affected / exposed	0 / 611 (0.00%)	1 / 305 (0.33%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 611 (0.33%)	1 / 305 (0.33%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	1 / 611 (0.16%)	0 / 305 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 611 (0.16%)	0 / 305 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	1 / 611 (0.16%)	0 / 305 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Vaxem Hib	Hiberix
Total subjects affected by non serious adverse events
subjects affected / exposed	247 / 611 (40.43%)	132 / 305 (43.28%)
General disorders and administration site conditions
Crying
subjects affected / exposed	22 / 611 (3.60%)	16 / 305 (5.25%)
occurrences all number	27	17
Pyrexia
subjects affected / exposed	73 / 611 (11.95%)	34 / 305 (11.15%)
occurrences all number	90	38
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	69 / 611 (11.29%)	36 / 305 (11.80%)
occurrences all number	73	41
Infections and infestations
Nasopharyngitis
subjects affected / exposed	87 / 611 (14.24%)	45 / 305 (14.75%)
occurrences all number	98	50
Upper respiratory tract infection
subjects affected / exposed	68 / 611 (11.13%)	36 / 305 (11.80%)
occurrences all number	84	42

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

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Clinical trials

Clinical Trial Results:
A Phase III, Observer-blind, randomized, controlled, multi-center study to inventigate the immunogenicity and safety of the Vaxem Hib™ in 2-4 months old healthy infants in China, according to the recommended regimen of 3 intramascular doses given one month apart.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 0.15 μg/mL at day 90

Primary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 0.15 μg/mL at day 90

Secondary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 1.0 μg/mL at day 90

Secondary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 1.0 μg/mL at day 90

Secondary: Geometric mean of anti-PRP antibody concentrations of Vaxem Hib and Hiberix groups at day 90

Secondary: Geometric mean of anti-PRP antibody concentrations of Vaxem Hib and Hiberix groups at day 90

Secondary: Number of Subjects Who Reported Local and Systemic Reactions After Each Vaccination of Vaxem Hib Vaccine or Hiberix vaccine.

Secondary: Number of Subjects Who Reported Local and Systemic Reactions After Each Vaccination of Vaxem Hib Vaccine or Hiberix vaccine.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Phase III, Observer-blind, randomized, controlled, multi-center study to inventigate the immunogenicity and safety of the Vaxem Hib™ in 2-4 months old healthy infants in China, according to the recommended regimen of 3 intramascular doses given one month apart.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 0.15 μg/mL at day 90

Primary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 0.15 μg/mL at day 90

Secondary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 1.0 μg/mL at day 90

Secondary: Percentage of subjects with the serum anti-PRP antibody titers ≥ 1.0 μg/mL at day 90

Secondary: Geometric mean of anti-PRP antibody concentrations of Vaxem Hib and Hiberix groups at day 90

Secondary: Geometric mean of anti-PRP antibody concentrations of Vaxem Hib and Hiberix groups at day 90

Secondary: Number of Subjects Who Reported Local and Systemic Reactions After Each Vaccination of Vaxem Hib Vaccine or Hiberix vaccine.

Secondary: Number of Subjects Who Reported Local and Systemic Reactions After Each Vaccination of Vaxem Hib Vaccine or Hiberix vaccine.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase III, Observer-blind, randomized, controlled, multi-center study to inventigate the immunogenicity and safety of the Vaxem Hib™ in 2-4 months old healthy infants in China, according to the recommended regimen of 3 intramascular doses given one month apart.