A Study of a Seasonal Trivalent Split, Inactivated Influenza Vaccine

• Sponsor: Institute of Virology, Vaccines and Sera, Torlak (Other)
• Overall Status: Completed
• CT.gov ID: NCT02585700
• Collaborator: Department of Health and Human Services (U.S. Fed), World Health Organization (Other), PATH (Other), Comac Medical (Industry)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 4
• Patients Per Site Per Month: 15.1

Study Details

Study Description

Brief Summary

This is a phase I, double-blind, randomized, placebo-controlled trial with two groups of participants to receive seasonal trivalent split, inactivated influenza vaccine (A/H1N1; A/H3N2 and B) or placebo (phosphate buffered saline). A total of 60 healthy male and female adults 18 through 45 years of age will be randomized to receive vaccine (30) or placebo (30).

Condition or Disease	Intervention/Treatment	Phase
Influenza, Human	Biological: Influenza vaccine, split inactivated; Other: Placebo	Phase 1

Detailed Description

This is a phase 1, double blinded, randomized, placebo-controlled study. The study will be conducted at 1 site in Serbia. Sixty (60) healthy male and female adults, 18 to 45 years of age, will be enrolled into the trial. Subjects will be randomized 1:1 to one of two treatment allocations: 30 to vaccine, 30 to placebo. The study will utilize a "randomized block design" to assure a balance of 1:1 vaccine and placebo when all subjects are enrolled. The study will be double blinded, meaning the study subjects, investigators, and the sponsor will be unaware of the treatment allocated to each subject until the clinical trial database is declared final and locked. The study should take about 5 months to complete, with each subject involved for 3 months from the day of injection. The justification for the 3 month follow up, rather than 6 month follow up is that this is an inactivated vaccine that follows very standard manufacturing practices with standard antigens. The safety of inactivated influenza vaccines is well-established. Adding length to the follow up results in delays in future testing of the vaccine for licensure.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Phase 1 Double Blinded, Randomized, Placebo-Controlled Study to Examine the Safety and Immunogenicity of a Seasonal Trivalent Split, Inactivated Influenza Vaccine Produced by Torlak in Healthy Adult Volunteers in Serbia
• Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: Mar 1, 2016
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vaccine 0.5 mL of influenza vaccine, split, inactivated with 15 mcg of haemagglutination (HA) of each of 3 strains: NYMC BX-51B reassortant of B/Massachusetts/2/2012 X-181 reassortant of H1/A/California/7/2009 X-223A reassortant of H3/A/Texas/50/2012.	Biological: Influenza vaccine, split inactivated; Seasonal trivalent inactivated influenza vaccine (TIV), inactivated split virion, purified by sucrose gradient ultracentrifugation. The vaccine is produced in hen's eggs, and inactivated with beta-propiolactone.
Placebo Comparator: Placebo 0.5 mL of phosphate buffered saline	Other: Placebo; 0.5 mL of phosphate buffered saline

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Immediate Adverse Events [30-minute post-vaccination period.]

   Number of subjects with observed immediate adverse events, including allergic reaction or anaphylaxis, following administration of the study product.

2. Number and Percentage of Subjects With Solicited Local Reactogenicity [7-day period (Days 0-6) post-vaccination.]

   Number of subjects reporting solicited local reactions (redness, swelling, induration, pain and tenderness) at the injection site post-vaccination with study vaccine or placebo

3. Number and Percentage of Subjects With Solicited Systemic Reactogenicity [7-day period (Days 0-6) post-vaccination.]

   Number of subjects reporting solicited systemic reactions (fever, fatigue/malaise, muscle aches, joint aches, chills, nausea, vomiting, and headache) post-vaccination with study vaccine or Placebo

4. Number and Percentage of Subjects With Occurrence of Unsolicited Adverse Events [Within 21 days post vaccination]

   These data are presented broadly as number per group for the study. Please see AE reporting section for more specific details on AEs.

5. Number and Percentage of Subjects With Occurrence of Serious Adverse Events (SAE) [Over the entire study period (Day 90).]

Secondary Outcome Measures

1. Number and Percentage of Seroconverted Subjects Against 3 Strains of Influenza Vaccine. [Day 21]

   Seroconversion is defined as a serum HAI titer meeting the following criteria: pre-vaccination titer <1:10 and a post-vaccination titer ≥ 1:40 or pre-vaccination titer ≥ 1:10 and at least a four-fold increase in post-vaccination measured on Day 21. The 3 influenza strains assessed were B/Massachusetts, H1/A/California and H3/A/Texas

2. Number and Percentage of Seroprotected Subjects Against 3 Strains of Influenza Vaccine [Day 0 and Day 21 post vaccination]

   A seroprotected subject was defined as a vaccinated subject who had a serum Hemagluttination Inhibition (HAI) titer ≥ 1:40. The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas

3. Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies Pre- (Day 0) and Post-vaccination (Day 21) for Each of the 3 Antigens [Pre- (Day 0) and post-vaccination (Day 21)]

   The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas

4. Geometric Mean Fold Rises (GMFRs) of Serum (HAI) Antibodies (Post-vaccination / Pre-vaccination) for Each of the 3 Antigens. [Pre- (Day 0) and post-vaccination (Day 21)]

   The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas

5. Geometric Mean Neutralization Titers of Neutralizing Antibodies (MNT) Pre- (Day 0) and Post-vaccination (Day 21) for Each of the 3 Antigens. [Pre- (Day 0) and post-vaccination (Day 21)]

6. Geometric Mean Fold Rises (GMFRs) of MNT (Post-vaccination / Pre-vaccination) for Each of the 3 Antigens. [Pre- (Day 0) and post-vaccination (Day 21)]

   The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male or female adult 18 through 45 years of age at the enrollment visit.

• Literate (by self-report) and willing to provide written informed consent.

• Healthy, as established by the medical history, physical examination, and screening laboratory evaluations.

• Capable and willing to complete Memory Aids and willing to return for all follow-up visits.

• For females, willing to utilize reliable birth control measures (e.g., intrauterine device, hormonal contraception, condoms) from Day 0 through the Day 21 visit.

Exclusion Criteria:

• Participation in another clinical trial involving any therapy within the previous three months or planned enrollment in such a trial during the period of this study.

• Receipt of any non-study vaccine within 4 weeks prior to enrollment or refusal to postpone receipt of such vaccines until after the Day 21 visit.

• Current or recent (within 2 weeks of vaccination) acute illness with or without fever.

• Receipt of immune globulin or other blood products within 3 months prior to study enrollment or planned receipt of such products prior to the Day 21 visit.

• Chronic administration (defined as more than 14 consecutively-prescribed days) of immunosuppressants or other immune-modulating therapy within six months prior to study vaccination. (For corticosteroids, this means prednisone or equivalent, equal or more than 0.5 mg per kg per day; topical steroids are allowed.)

• History of asthma.

• Hypersensitivity after previous administration of any vaccine.

• Suspected or known hypersensitivity to any of the study vaccine components, including chicken or egg protein.

• Acute or chronic clinically significant pulmonary, cardiovascular, hepatobiliary, metabolic, neurologic, psychiatric or renal functional abnormality, as determined by medical history, physical examination or clinical laboratory screening tests, which in the opinion of the investigator, might interfere with the study objectives.

• History of any blood or solid organ cancer.

• History of thrombocytopenic purpura or known bleeding disorder.

• History of seizures.

• Known or suspected immunosuppressed or immunodeficient condition of any kind.

• Confirmed hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

• Known HIV infection (self-report).

• Known active tuberculosis or symptoms of active tuberculosis, regardless of cause (self-report).

• History of chronic alcohol abuse and/or illegal drug use.

• Pregnancy or lactation. (A negative pregnancy test will be required before administration of study product for all women of childbearing potential.)

• History of Guillain-Barré Syndrome

• Any condition that, in the opinion of the investigator, would increase the health risk to the subject if he/she participates in the study or would interfere with the evaluation of the study objectives.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Center of Serbia	Belgrade		Serbia

Sponsors and Collaborators

• Institute of Virology, Vaccines and Sera, Torlak
• Department of Health and Human Services
• World Health Organization
• PATH
• Comac Medical

Investigators

• Principal Investigator: Goran Stevanovic, PhD, Clinic for Infectious and Tropical Diseases

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Institute of Virology, Vaccines and Sera, Torlak
• ClinicalTrials.gov Identifier: NCT02585700
• Other Study ID Numbers: TORLAK-100
• First Posted: Oct 23, 2015
• Last Update Posted: Jan 15, 2019
• Last Verified: Oct 1, 2015

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Institute of Virology, Vaccines and Sera, Torlak: Grippe; Human Flu; Human influenza
• Additional relevant MeSH terms: Influenza, Human

Study Results

Participant Flow

Recruitment Details	All volunteers were recruited at the Clinical Center of Serbia, Belgrade, Serbia.
Pre-assignment Detail	66 people were screened for the study after signing consent. 6 subjects failed screening. A total of 60 subjects received vaccine or placebo.

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Period Title: Overall Study
STARTED	30	30
COMPLETED	30	30
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Vaccine Group	Placebo Group	Total
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline	Total of all reporting groups
Overall Participants	30	30	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.00 (7.21)	30.70 (6.14)	30.85 (6.64)
Sex: Female, Male (Count of Participants)
Female	9 30%	9 30%	18 30%
Male	21 70%	21 70%	42 70%
Race/Ethnicity, Customized (Count of Participants)
White	30 100%	30 100%	60 100%
Other	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Serbia	30 100%	30 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Immediate Adverse Events
Description	Number of subjects with observed immediate adverse events, including allergic reaction or anaphylaxis, following administration of the study product.
Time Frame	30-minute post-vaccination period.

Outcome Measure Data

Analysis Population Description

The analysis was conducted for subjects who were randomized and received a study vaccination

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
Count of Participants [Participants]	0 0%	0 0%

2. Primary Outcome

Title	Number and Percentage of Subjects With Solicited Local Reactogenicity
Description	Number of subjects reporting solicited local reactions (redness, swelling, induration, pain and tenderness) at the injection site post-vaccination with study vaccine or placebo
Time Frame	7-day period (Days 0-6) post-vaccination.

Outcome Measure Data

Analysis Population Description

The analysis was conducted for subjects who were randomized and received a study vaccination

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
Hardness	2 6.7%	0 0%
Pain	14 46.7%	4 13.3%
Redness	6 20%	0 0%
Swelling	2 6.7%	0 0%
Tenderness	10 33.3%	1 3.3%

3. Primary Outcome

Title	Number and Percentage of Subjects With Solicited Systemic Reactogenicity
Description	Number of subjects reporting solicited systemic reactions (fever, fatigue/malaise, muscle aches, joint aches, chills, nausea, vomiting, and headache) post-vaccination with study vaccine or Placebo
Time Frame	7-day period (Days 0-6) post-vaccination.

Outcome Measure Data

Analysis Population Description

The analysis was conducted for subjects who were randomized and received a study vaccination

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
Temperature above 37 C	2 6.7%	1 3.3%
Chills	2 6.7%	0 0%
Headache	5 16.7%	2 6.7%
Joint aches	1 3.3%	2 6.7%
Muscle aches	2 6.7%	1 3.3%
Nausea	2 6.7%	0 0%
Tiredness	5 16.7%	0 0%
Vomiting	1 3.3%	0 0%

4. Primary Outcome

Title	Number and Percentage of Subjects With Occurrence of Unsolicited Adverse Events
Description	These data are presented broadly as number per group for the study. Please see AE reporting section for more specific details on AEs.
Time Frame	Within 21 days post vaccination

Outcome Measure Data

Analysis Population Description

The analysis was conducted for subjects who were randomized and received a study vaccination

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
Count of Participants [Participants]	2 6.7%	4 13.3%

5. Primary Outcome

Title	Number and Percentage of Subjects With Occurrence of Serious Adverse Events (SAE)
Time Frame	Over the entire study period (Day 90).

Outcome Measure Data

Analysis Population Description

The analysis was conducted for subjects who were randomized and received a study vaccination

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
Serious adverse events (SAEs)--related	0 0%	0 0%
SAEs--not related	0 0%	0 0%

6. Secondary Outcome

Title	Number and Percentage of Seroconverted Subjects Against 3 Strains of Influenza Vaccine.
Description	Seroconversion is defined as a serum HAI titer meeting the following criteria: pre-vaccination titer <1:10 and a post-vaccination titer ≥ 1:40 or pre-vaccination titer ≥ 1:10 and at least a four-fold increase in post-vaccination measured on Day 21. The 3 influenza strains assessed were B/Massachusetts, H1/A/California and H3/A/Texas
Time Frame	Day 21

Outcome Measure Data

Analysis Population Description

The analysis was conducted for subjects who were randomized and received a study vaccination

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
Seroconversion to H1	25 83.3%	0 0%
Seroconversion to H3	23 76.7%	0 0%
Seroconversion to B	21 70%	0 0%

7. Secondary Outcome

Title	Number and Percentage of Seroprotected Subjects Against 3 Strains of Influenza Vaccine
Description	A seroprotected subject was defined as a vaccinated subject who had a serum Hemagluttination Inhibition (HAI) titer ≥ 1:40. The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas
Time Frame	Day 0 and Day 21 post vaccination

Outcome Measure Data

Analysis Population Description

All vaccinated subjects who have valid post vaccination immunogenicity measures with no major protocol violations

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
H1	30 100%	10 33.3%
H3	30 100%	19 63.3%
B	26 86.7%	5 16.7%

8. Secondary Outcome

Title	Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies Pre- (Day 0) and Post-vaccination (Day 21) for Each of the 3 Antigens
Description	The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas
Time Frame	Pre- (Day 0) and post-vaccination (Day 21)

Outcome Measure Data

Analysis Population Description

All vaccinated subjects with no major protocol violations who have valid post vaccination immunogenicity measures

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
GMT to H1 Day 0	15.97	21.19
GMT to H1 Day 21	295.14	22.32
GMT to H3 Day 0	37.75	41.41
GMT to H3 Day 21	439.67	42.87
GMT to B Day 0	10.47	10.72
GMT to B Day 21	75.95	10.66

9. Secondary Outcome

Title	Geometric Mean Fold Rises (GMFRs) of Serum (HAI) Antibodies (Post-vaccination / Pre-vaccination) for Each of the 3 Antigens.
Description	The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas
Time Frame	Pre- (Day 0) and post-vaccination (Day 21)

Outcome Measure Data

Analysis Population Description

All vaccinated subjects who have valid post vaccination immunogenicity measures with no major protocol violations

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
GMFR for H1	18.49	1.05
GMFR for H3	11.65	1.04
GMFR for B	7.25	0.99

10. Secondary Outcome

Title	Geometric Mean Neutralization Titers of Neutralizing Antibodies (MNT) Pre- (Day 0) and Post-vaccination (Day 21) for Each of the 3 Antigens.
Time Frame	Pre- (Day 0) and post-vaccination (Day 21)

Outcome Measure Data

Analysis Population Description

All vaccinated subjects who have valid post vaccination immunogenicity measures with no major protocol violations

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
GMT to H1 Day 0	24.06	31.75
GMT to H1 Day 21	211.12	40.00
GMT to H3 Day 0	18.02	19.77
GMT to H3 Day 21	125.53	24.34
GMT to B Day 0	80.93	70.45
GMT to B Day 21	331.28	105.56

11. Secondary Outcome

Title	Geometric Mean Fold Rises (GMFRs) of MNT (Post-vaccination / Pre-vaccination) for Each of the 3 Antigens.
Description	The 3 influenza strains assessed were B/Massachusetts, H1/A/California an d H3/A/Texas
Time Frame	Pre- (Day 0) and post-vaccination (Day 21)

Outcome Measure Data

Analysis Population Description

All vaccinated subjects who have valid post vaccination immunogenicity measures with no major protocol violations

Arm/Group Title	Vaccine Group	Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine split, inactivated with 15 mcg of HA of B/Massachusetts, H1/A/California, and H3/A/Texas	0.5 mL of phosphate buffered saline
Measure Participants	30	30
GMFR for H1	8.77	1.26
GMFR for H3	6.96	1.23
GMFR for B	4.09	1.50

Adverse Events

Time Frame	90 days
Arm/Group Title	Vaccine Group		Placebo Group
Arm/Group Description	0.5 mL of influenza vaccine, split, inactivated with 15 mcg of HA of each of 3 strains: NYMC BX-51B reassortant of B/Massachusetts/2/2012 X-181 reassortant of H1/A/California/7/2009 X-223A reassortant of H3/A/Texas/50/2012.		0.5 mL of phosphate buffered saline
All Cause Mortality
	Vaccine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Serious Adverse Events
	Vaccine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Vaccine Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/30 (6.7%)		4/30 (13.3%)
Gastrointestinal disorders
Diarrhea	0/30 (0%)		1/30 (3.3%)
Investigations
Alanine Aminotransferase Increased	0/30 (0%)		1/30 (3.3%)
Musculoskeletal and connective tissue disorders
Back Pain	1/30 (3.3%)		1/30 (3.3%)
Respiratory, thoracic and mediastinal disorders
Respiratory Tract Infection	1/30 (3.3%)		0/30 (0%)
Cough	0/30 (0%)		1/30 (3.3%)

Limitations/Caveats

No limitations

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.