Evaluating the Comparative Safety and Immunogenicity of Three Lots of Novartis Meningococcal C Conjugate Vaccine in Healthy Toddlers

• Sponsor: Novartis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01434680
• Collaborator: Novartis Vaccines (Industry)
• Enrollment: 992
• Locations: 11
• Arms: 3
• Duration (Months): 14
• Patients Per Site: 90.2
• Patients Per Site Per Month: 6.4

Study Details

Study Description

Brief Summary

The study was to evaluate the safety and and immune response of each of three lots of Novartis Meningococcal C Conjugate Vaccine (MenC-CRM Liquid) when administered to Healthy Toddlers.

Condition or Disease	Intervention/Treatment	Phase
Meningococcal Disease; Meningococcal Meningitis	Biological: MenC-CRM LIQ; Biological: MenC-CRM ROS; Biological: MenC-CRM EMV	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 992 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Prevention
• Official Title: A Phase 2, Randomized, Comparative, Multicenter Observer-Blind Study Evaluating the Safety and Immunogenicity of the New Liquid Formulation of Novartis Meningococcal C Conjugate Vaccine and of the Novartis Lyophilized Meningococcal C Conjugate Vaccine Manufactured at Two Different Sites, in Healthy Toddlers
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MenC-CRM LIQ (Liquid Formulation) Subjects received 1 injection of MenC-CRM vaccine,liquid formulation.	Biological: MenC-CRM LIQ; One dose of MenC-CRM vaccine, liquid formulation
Experimental: MenC-CRM ROS (Rosia) Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy	Biological: MenC-CRM ROS; One dose of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy.
Active Comparator: MenC-CRM EMV (Emeryville) Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Emeryville, USA	Biological: MenC-CRM EMV; One dose of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Emeryville, USA.

Outcome Measures

Primary Outcome Measures

1. Geometric Mean Human Serum Bactericidal Activity Titers Against N Meningitidis Serogroup C 28 Days After Vaccination [1 month postvaccination (day 29)]

   Immunogenicity was measured by human serum bactericidal activity (hSBA) geometric mean titers (GMTs)against N meningitidis type C, at day 29 after a single vaccination when administered to toddlers to assess the equivalence of MenC-CRM LIQ to MenC-CRM EMV and MenC-CRM ROS to MenC-CRM EMV.

Secondary Outcome Measures

1. Geometric Mean hSBA Titers Against N Meningitidis Serogroup C 28 Days After Vaccination [1 month postvaccination (day 29)]

   Immunogenicity was measured by hSBA GMTs against N meningitidis type C, approximately 28 days (at day 29) after a single vaccination when administered to toddlers to assess the equivalence of MenC-CRM LIQ to MenC-CRM ROS.

2. Number Of Subjects Reporting Solicited Local And Systemic Adverse Events [From day 1 through day 7]

   Safety was assessed as the number of subjects who reported solicited local and systemic adverse events following a single injection with either MenC-CRM LIQ or MenC-CRM ROS or MenC-CRM EMV. Safety was also assessed in subjects who mistakenly received MenC-CRM EMV instead of MenC-CRM ROS.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Months to 23 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Healthy 12 - 23 (inclusive) month-old male or female toddlers.

2. A parent/legal guardian was given written informed consent after the nature of the study has been explained.

3. Available for both the visits scheduled in the study.

4. In good health as determined by medical history, physical examination and clinical judgment of the investigator.

Exclusion Criteria:

1. History of any meningococcal vaccine administration.

2. Previous known or suspected disease caused by N. meningitidis.

3. Household contact with and/or intimate exposure to an individual with laboratory confirmed N. meningitidis infection or colonization.

4. History of severe allergic reaction after previous vaccinations, allergy to Latex, or hypersensitivity to any component of the vaccine.

5. Significant acute or chronic infection within the previous 7 days or axillary temperature ≥38.0°C within the previous 3 days.

6. Individuals who have received antibiotics within 6 days before vaccination.

7. Known or suspected autoimmune disease or impairment/alteration of the immune system resulting from (for example):

• Receipt of any immunosuppressive therapy at any time since birth.

• Receipt of any immunostimulants at any time since birth.

• Receipt of any systemic corticosteroids or chronic use of inhaled high-potency corticosteroids since birth (use of topical corticosteroids administered in limited areas of the body [for example, eczema on knees or face or elbows] is allowed).

• Immune deficiency disorder, or known HIV infection.

1. History of seizure, any progressive neurological disease or Guillain Barré Syndrome (exception: one self-limited non-medicated febrile seizure is acceptable).

2. Known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.

3. Receipt of blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the past 12 weeks.

4. Taken any antipyretic medication in the previous 6 hours.

5. Received any other vaccines within 30 days prior to enrollment or intent to receive any other vaccine during the study (Exception: Inactivated influenza vaccine may be administered up to 15 days prior to study immunization and no less than 15 days after study immunization).

6. Toddler's parent(s) or legal guardian(s) are not able to comprehend and to follow all required study procedures for the whole period of the study.

7. Participation in any clinical trial with another investigational product 30 days prior to first study visit or intent to participate in another clinical study during this study.

8. Family members or household members of site research staff.

9. History or any illness/condition that, in the opinion of the investigator, might interfere with the results of the study or pose additional risk to the subjects due to participation in the study.

10. Any serious chronic or progressive disease according to judgment of the investigator (neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NZOZ Bioscience Sp zoo	ul Czerkaska	Bydgoszcz	Poland
2	Department Infection Disease ZOZ	Dept Infection Disease ZOZ	Debica	Poland
3	Centrum Medyczne Graniczna Sp zoo	ul Graniczna 45	Katowice	Poland
4	NZOZ HIPOKRATES IIspzoo	Ul Strzelecka 2	Krakow	Poland
5	Wojewodzki Specjalistyczny Szpital im dr Wl Bieganskiego	ul. Kniaziewicza 1-5	Lodz	Poland
6	Specjalistyczny Zespol	Ul Krysiewicza	Poznan	Poland
7	NZLA Michalkowice Jarosz i Partnerzy Spolka Lekarska	NZLA Michalkowice Jarosz Partnerzy Spolka Lekarska	Siemianowice Slaskie	Poland
8	Zespol Przychodni Specjalistycznych SP ZOZ w Tarnowie	E Szczeklik Hospital	Tarnów	Poland
9	Samodzielny Zespol Publicznych Zakladow Opieki Zdrowotnej w	Ul Prusicka 5355	Trzebnica	Poland
10	Klinika Pediatrii Centrum Medycznego Ksztalcenia Podyplomowe	Ceglowska 80	Warszawa	Poland
11	Amicur_Krystyna Lechka-Florianska i Partnerzy	Ul O Bujwida	Wroclaw	Poland

Sponsors and Collaborators

• Novartis
• Novartis Vaccines

Investigators

• Study Chair: Novartis Vaccines, Novartis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT01434680
• Other Study ID Numbers: V14_57
• First Posted: Sep 15, 2011
• Last Update Posted: Apr 25, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Novartis: Meningococcal disease; vaccines; toddlers; prevention; Meningitis
• Additional relevant MeSH terms: Meningococcal Infections; Meningitis, Meningococcal; Meningitis

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled at eleven sites in Poland.
Pre-assignment Detail	All enrolled subjects were included in the trial. Data from the group MenC-CRM ROS_EMV was not included in the primary and secondary analyses as these subjects were initially enrolled in group MenC-CRM ROS, but wrongly vaccinated with MenC-CRM EMV.

Arm/Group Title	MenC-CRM LIQ	MenC-CRM ROS	MenC-CRM EMV	MenC-CRM ROS_EMV
Arm/Group Description	Subjects received 1 injection of MenC-CRM vaccine, liquid formulation.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Emeryville, USA.	Subjects enrolled to receive MenC-CRM ROS, but were mistakenly administered 1 injection of MenC-CRM EMV
Period Title: Overall Study
STARTED	299	268	306	119
COMPLETED	296	266	304	119
NOT COMPLETED	3	2	2	0

Baseline Characteristics

Arm/Group Title	MenC-CRM LIQ	MenC-CRM ROS	MenC-CRM EMV	MenC-CRM ROS_EMV	Total
Arm/Group Description	Subjects received 1 injection of MenC-CRM vaccine, liquid formulation.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Emeryville, USA.	Subjects enrolled to receive MenC-CRM ROS, but were mistakenly administered 1 injection of MenC-CRM EMV	Total of all reporting groups
Overall Participants	299	268	306	119	992
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	16.4 (3.4)	16.2 (3.2)	16.7 (3.4)	17.2 (3.3)	16.5 (3.3)
Sex: Female, Male (Count of Participants)
Female	143 47.8%	131 48.9%	141 46.1%	50 42%	465 46.9%
Male	156 52.2%	137 51.1%	165 53.9%	69 58%	527 53.1%

Outcome Measures

1. Primary Outcome

Title	Geometric Mean Human Serum Bactericidal Activity Titers Against N Meningitidis Serogroup C 28 Days After Vaccination
Description	Immunogenicity was measured by human serum bactericidal activity (hSBA) geometric mean titers (GMTs)against N meningitidis type C, at day 29 after a single vaccination when administered to toddlers to assess the equivalence of MenC-CRM LIQ to MenC-CRM EMV and MenC-CRM ROS to MenC-CRM EMV.
Time Frame	1 month postvaccination (day 29)

Outcome Measure Data

Analysis Population Description

Analysis was done on the per protocol (PP) set, i.e. the subjects who received the vaccine correctly; provided evaluable serum samples at the relevant time points; and had no major protocol violations as defined prior to analysis.

Arm/Group Title	MenC-CRM LIQ	MenC-CRM ROS	MenC-CRM EMV
Arm/Group Description	Subjects received 1 injection of MenC-CRM vaccine, liquid formulation.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Emeryville, USA.
Measure Participants	283	259	281
Day 1	2.1	2.16	2.15
Day 29	9.84	14	12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MenC-CRM LIQ, MenC-CRM EMV
	Comments	The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing MenC-CRM LIQ to MenC-CRM EMV at 28 days after a single vaccination were both within the equivalence interval (0.5, 2.0).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The equivalence margin was (0.5, 2.0). If the two-sided 95% CI for the ratio of the hSBA GMTs at 28 days following vaccination was within this equivalence interval for each of the two coprimary comparisons, MenC-CRM LIQ and MenC-CRM EMV would be declared equivalent with respect to the immune response to the vaccines.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments	95% CIs for the GMTs ratios was obtained by exponentiating difference of least square means of log10 transformed titers and both the limits of 95% CIs
Method of Estimation	Estimation Parameter	hSBA GMT ratios
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MenC-CRM ROS, MenC-CRM EMV
	Comments	The study would be considered a success if the two-sided 95% confidence intervals (CIs) for the hSBA GMT ratios comparing MenC-CRM ROS to MenC-CRM EMV at 28 days after a single vaccination were both within the equivalence interval (0.5, 2.0).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The equivalence margin was (0.5, 2.0). If the two-sided 95% CI for the ratio of the hSBA GMTs at 28 days following vaccination was within this equivalence interval for each of the two coprimary comparisons,MenC-CRM ROS and MenC-CRM EMV would be declared equivalent with respect to the immune response to the vaccines.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments	95% CIs for the GMTs ratios was obtained by exponentiating difference of least square means of log10-transformed titers and both the limits of 95% CIs
Method of Estimation	Estimation Parameter	hSBA GMT ratios
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Geometric Mean hSBA Titers Against N Meningitidis Serogroup C 28 Days After Vaccination
Description	Immunogenicity was measured by hSBA GMTs against N meningitidis type C, approximately 28 days (at day 29) after a single vaccination when administered to toddlers to assess the equivalence of MenC-CRM LIQ to MenC-CRM ROS.
Time Frame	1 month postvaccination (day 29)

Outcome Measure Data

Analysis Population Description

Analysis was done on the per protocol (PP) set.

Arm/Group Title	MenC-CRM LIQ	MenC-CRM ROS
Arm/Group Description	Subjects received 1 injection of MenC-CRM vaccine, liquid formulation.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy.
Measure Participants	283	259
Day 1	2.1	2.16
Day 29	9.84	14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MenC-CRM LIQ, MenC-CRM ROS
	Comments	The secondary objective was to be assessed only if both primary objectives were met. Because of this, no adjustment for multiplicity was required. MenC-CRM liquid would be declared equivalent to MenC-CRM ROS if the two-sided 95% CI for the ratio of the hSBA GMTs at approximately 28 days following vaccination was within the equivalence interval (0.5, 2.0).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The equivalence margin was (0.5, 2.0). If the two-sided 95% CI for the ratio of the hSBA GMTs at 28 days following vaccination was within this equivalence interval, the two vaccine groups would be declared equivalent with respect to the immune response to the vaccines.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments	95% CIs for the GMTs ratios was obtained by exponentiating difference of least square means of log10-transformed titers and both the limits of 95% CIs
Method of Estimation	Estimation Parameter	hSBA GMT ratios
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number Of Subjects Reporting Solicited Local And Systemic Adverse Events
Description	Safety was assessed as the number of subjects who reported solicited local and systemic adverse events following a single injection with either MenC-CRM LIQ or MenC-CRM ROS or MenC-CRM EMV. Safety was also assessed in subjects who mistakenly received MenC-CRM EMV instead of MenC-CRM ROS.
Time Frame	From day 1 through day 7

Outcome Measure Data

Analysis Population Description

Analysis was done on the safety dataset, i.e. the subjects in the exposed population who provided postvaccination safety data.

Arm/Group Title	MenC-CRM LIQ	MenC-CRM ROS	MenC-CRM EMV	MenC-CRM ROS_EMV
Arm/Group Description	Subjects received 1 injection of MenC-CRM vaccine, liquid formulation.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy.	Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Emeryville, USA.	Subjects enrolled to receive MenC-CRM ROS, but were mistakenly administered 1 injection of MenC-CRM EMV
Measure Participants	299	267	304	119
Any Local	124	115	148	58
Injection site Tenderness	88	64	101	41
Injection site Erythema	222	200	211	81
Injection site Induration	252	227	236	88
Any Systemic	163	140	155	60
Change in Eating habits	87	68	83	26
Sleepiness	66	55	56	24
Persistent Crying	45	41	36	15
Vomiting	9	11	7	4
Diarrhea	42	30	34	17
Irritability	101	76	87	32
Fever (≥38°C)	20	11	18	13

Adverse Events

Time Frame	Solicited local and systemic adverse events from day 1 to 7. Serious adverse events (SAEs) and Unsolicited AEs (other than SAEs) from day 1 to day 29 (1 month after first vaccination).
Adverse Event Reporting Description	All Solicited AEs are classified as systematic assessment and all unsolicited AEs are classified as non-systematic assessment.
Arm/Group Title	MenC-CRM LIQ		MenC-CRM ROS		MenC-CRM EMV		MenC-CRM ROS_EMV
Arm/Group Description	Subjects received 1 injection of MenC-CRM vaccine, liquid formulation.		Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Rosia, Italy.		Subjects received 1 injection of MenC-CRM vaccine, lyophilized formulation produced with drug substance manufactured at Emeryville, USA.		Subjects enrolled to receive MenC-CRM ROS, but were mistakenly administered 1 injection of MenC-CRM EMV
All Cause Mortality
	MenC-CRM LIQ		MenC-CRM ROS		MenC-CRM EMV		MenC-CRM ROS_EMV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MenC-CRM LIQ		MenC-CRM ROS		MenC-CRM EMV		MenC-CRM ROS_EMV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/299 (0%)		3/267 (1.1%)		2/304 (0.7%)		1/119 (0.8%)
Gastrointestinal disorders
Diarrhea	0/299 (0%)		0/267 (0%)		1/304 (0.3%)		1/119 (0.8%)
Vomiting	0/299 (0%)		0/267 (0%)		1/304 (0.3%)		0/119 (0%)
Infections and infestations
Gastroenteritis Rotavirus	0/299 (0%)		2/267 (0.7%)		0/304 (0%)		0/119 (0%)
Pneumonia	0/299 (0%)		1/267 (0.4%)		1/304 (0.3%)		0/119 (0%)
Other (Not Including Serious) Adverse Events
	MenC-CRM LIQ		MenC-CRM ROS		MenC-CRM EMV		MenC-CRM ROS_EMV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	252/299 (84.3%)		227/267 (85%)		236/304 (77.6%)		88/119 (73.9%)
Gastrointestinal disorders
Diarrhea	44/299 (14.7%)		32/267 (12%)		36/304 (11.8%)		17/119 (14.3%)
General disorders
Crying	45/299 (15.1%)		41/267 (15.4%)		36/304 (11.8%)		15/119 (12.6%)
Injection Site Erythema	222/299 (74.2%)		200/267 (74.9%)		211/304 (69.4%)		81/119 (68.1%)
Injection Site Induration	252/299 (84.3%)		227/267 (85%)		236/304 (77.6%)		88/119 (73.9%)
Injection Site Pain	88/299 (29.4%)		64/267 (24%)		101/304 (33.2%)		41/119 (34.5%)
Irritability	101/299 (33.8%)		76/267 (28.5%)		87/304 (28.6%)		32/119 (26.9%)
Pyrexia	27/299 (9%)		15/267 (5.6%)		23/304 (7.6%)		17/119 (14.3%)
Infections and infestations
Respiratory Tract Infection	10/299 (3.3%)		7/267 (2.6%)		12/304 (3.9%)		6/119 (5%)
Nervous system disorders
Somnolence	66/299 (22.1%)		55/267 (20.6%)		56/304 (18.4%)		24/119 (20.2%)
Psychiatric disorders
Eating Disorder	88/299 (29.4%)		68/267 (25.5%)		83/304 (27.3%)		26/119 (21.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.