MI-MA205: A Prospective Study to Evaluate the Safety of a New Monovalent Intranasal Influenza Vaccine

• Sponsor: MedImmune LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00873912
• Collaborator: (none)
• Enrollment: 300
• Locations: 3
• Arms: 2
• Duration (Months): 7
• Patients Per Site: 100
• Patients Per Site Per Month: 14.2

Study Details

Study Description

Brief Summary

This prospective annual release study was designed to assess the safety of a monovalent influenza virus vaccine using a new strain recommended for the 2009-2010 influenza season not previously contained in the trivalent intranasal FluMist vaccine. Three hundred healthy adults received a single dose of vaccine or placebo and were followed for 180 days.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Biological: Monovalent influenza virus vaccine; Biological: Placebo	Phase 4

Detailed Description

This prospective, randomized, double-blind, placebo-controlled release study enrolled 300 healthy adults 18 to 49 years of age. Eligible participants were randomly assigned in a 4:1 fashion to receive a single dose of monovalent vaccine or placebo by intranasal spray. This study was conducted at multiple sites in the United States. Randomization was stratified by site.

Each participant received one dose of investigational product on Day 1. The duration of study participation for each participant was the time from receipt of investigational product through 180 days after receipt of investigational product.

Study Design

• Study Type: Interventional
• Actual Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety of a New 6:2 Influenza Virus Reassortant in Healthy Adults
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Monovalent influenza virus vaccine Frozen monovalent vaccine containing new strain	Biological: Monovalent influenza virus vaccine; Monovalent vaccine was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 FFU (fluorescent focus units) of the cold-adapted, attenuated, 6:2 reassortant influenza strain B/Brisbane/60/2008 (Victoria lineage).
Placebo Comparator: Placebo Placebo	Biological: Placebo; Placebo was supplied in intranasal sprayers containing 0.5 mL of sucrose-phosphate buffer.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Reporting Fever, Defined as Oral Temperature ≥ 101°F [Days 1-8 after vaccination]

   The percentage of subjects with fever was compared between the two treatment groups based on the upper limit of the two-sided 95% exact confidence interval (CI) for the rate difference (monovalent vaccine minus placebo). The upper limit of the two-sided 95% CI was evaluated against the pre-specified equivalence criterion of 5 percentage points which corresponded to the following hypotheses: - H0 (null): rate difference ≥ 5 percentage points, - HA (alternative): rate difference < 5 percentage points.

Secondary Outcome Measures

1. Number of Participants Reporting Any Solicited Symptom or at Least One Adverse Event (AE) [Days 1-8 after vaccination]

   Solicited symptoms were collected from administration of investigational product through Study Day 15. For this study, solicited symptoms included: fever (> 100°F oral), runny nose, sore throat, cough, vomiting, muscle aches, chills, decreased activity (tiredness), headache.

2. Number of Participants Reporting Any Solicited Symptom or at Least One AE [Days 1-15 after vaccination]

3. Number of Participants Reporting at Least One Serious Adverse Event (SAE) or New Onset Chronic Disease (NOCD) [Days 1-29 after vaccination]

   SAEs were those that resulted in death; were life-threatening; resulted in inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; were a congenital anomaly/birth defect in the offspring of a study participant; or were an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed above. An NOCD was a newly diagnosed medical condition of a chronic, ongoing nature and assessed by the investigator as medically significant.

4. Number of Participants Reporting at Least One Serious Adverse Event (SAE) or New Onset Chronic Disease (NOCD) [Days 1-181 after vaccination]

   SAEs were those that resulted in death; were life-threatening; resulted in inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; were a congenital anomaly/birth defect in the offspring of a study participant; or were an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed above. An NOCD was a newly diagnosed medical condition of a chronic, ongoing nature and assessed by the investigator as medically significant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 49 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Male or female, 18 to 49 years of age (not yet reached their 50th birthday) at the time of investigational product administration

• Healthy by medical history and physical exam

• Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act [HIPAA] in the United States of America [USA], European Union [EU] Data Privacy Directive in the EU) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations

• Females of childbearing potential, unless surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy), had sterile male partner, were premenarchal or at least 2 years postmenopausal, or practiced abstinence, must have used 2 effective methods of avoiding pregnancy (including oral, transdermal, or implanted contraceptives, intrauterine device, female condom with spermicide, diaphragm with spermicide, cervical cap, or use of a condom with spermicide by the sexual partner) for at least 30 days prior to dosing with investigational product, and must have agreed to continue using such precautions for at least 90 days after dosing with investigational product; cessation of birth control after this point was to be discussed with a responsible physician. The subject must also have had a negative serum or urine pregnancy test within 14 days prior to investigational product administration (if screening and administration of investigational product did not occur on the same day) and on the day of investigational product administration prior to randomization

• Males, unless surgically sterile, must have used 2 effective methods of birth control with a female partner and must have agreed to continue using such contraceptive precautions for at least 30 days after dosing with investigational product (from Day 1 through Day 31 of the study)

• Subject available by telephone

• Ability to understand and comply with the requirements of the protocol, as judged by the investigator

• Ability to complete follow-up period of 180 days after dosing as required by the protocol

Exclusion Criteria:

• History of hypersensitivity to any component of the vaccine, including egg or egg protein or serious, life-threatening, or severe reactions to previous influenza vaccinations

• History of hypersensitivity to gentamicin

• Any condition for which the inactivated influenza vaccine was indicated, including chronic disorders of the pulmonary or cardiovascular systems (eg, asthma), chronic metabolic diseases (eg, diabetes mellitus), renal dysfunction, or hemoglobinopathies that required regular medical follow-up or hospitalization during the preceding year

• Acute febrile (> 100.0°F oral or equivalent) and/or clinically significant respiratory illness (eg, cough or sore throat) within 14 days prior to randomization

• Any known immunosuppressive condition or immune deficiency disease, including human immunodeficiency virus [HIV] infection, or ongoing immunosuppressive therapy

• History of Guillain-Barré syndrome

• A household contact who was severely immunocompromised (eg, hematopoietic stem cell transplant recipient, during those periods in which the immunocompromised individual required care in a protective environment); subject should additionally have avoided close contact with severely immunocompromised individuals for at least 21 days after receipt of investigational product

• Receipt of any investigational agent within 30 days prior to randomization, or expected receipt through 30 days after the dose of investigational product (use of licensed agents for indications not listed in the package insert was permitted)

• Expected receipt of anti-pyretic or analgesic medication on a daily or every other day basis from randomization through 14 days after receipt of investigational product

• Administration of intranasal medications within 14 days prior to randomization, or expected receipt through 14 days after administration of investigational product

• Known or suspected mitochondrial encephalomyopathy

• Nursing mother

• Any condition (eg, chronic cough, allergic rhinitis) that, in the opinion of the investigator, would have interfered with evaluation of the investigational product or interpretation of subject safety or study results

• Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance CRU, Inc.	Daytona Beach	Florida	United States	32117
2	Covance CRU, Inc	Portland	Oregon	United States	97239
3	Covance CRU, Inc	Austin	Texas	United States	78757

Sponsors and Collaborators

• MedImmune LLC

Investigators

• Study Director: Elissa Malkin, D.O., MedImmune LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00873912
• Other Study ID Numbers: MI-MA205
• First Posted: Apr 2, 2009
• Last Update Posted: Jul 14, 2011
• Last Verified: Jul 1, 2011

• Keywords provided by , ,: influenza; FluMist
• Additional relevant MeSH terms: Influenza, Human

Study Results

Participant Flow

Recruitment Details	A total of 300 subjects were randomized into the study between 26May2009 and 27May2009 at 3 sites in the USA.
Pre-assignment Detail	Each site enrolled and randomized 80 subjects in the monovalent vaccine group and 20 subjects in the placebo group

Arm/Group Title	Monovalent Influenza Virus Vaccine	Placebo
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.	Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.
Period Title: Overall Study
STARTED	240	60
COMPLETED	237	60
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Monovalent Influenza Virus Vaccine	Placebo	Total
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.	Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.	Total of all reporting groups
Overall Participants	240	60	300
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.2 (8.1)	30.9 (8.6)	31.9 (8.2)
Sex: Female, Male (Count of Participants)
Female	124 51.7%	33 55%	157 52.3%
Male	116 48.3%	27 45%	143 47.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	36 15%	10 16.7%	46 15.3%
Not Hispanic or Latino	204 85%	50 83.3%	254 84.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (participants) [Number]
American Indian or Alaska Native	7 2.9%	2 3.3%	9 3%
Asian	2 0.8%	2 3.3%	4 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	18 7.5%	5 8.3%	23 7.7%
White	206 85.8%	50 83.3%	256 85.3%
More than one race	4 1.7%	1 1.7%	5 1.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Other	3 1.3%	0 0%	3 1%
Region of Enrollment (participants) [Number]
United States	240 100%	60 100%	300 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting Fever, Defined as Oral Temperature ≥ 101°F
Description	The percentage of subjects with fever was compared between the two treatment groups based on the upper limit of the two-sided 95% exact confidence interval (CI) for the rate difference (monovalent vaccine minus placebo). The upper limit of the two-sided 95% CI was evaluated against the pre-specified equivalence criterion of 5 percentage points which corresponded to the following hypotheses: - H0 (null): rate difference ≥ 5 percentage points, - HA (alternative): rate difference < 5 percentage points.
Time Frame	Days 1-8 after vaccination

Outcome Measure Data

Analysis Population Description

The Safety Population includes all subjects who received at least one dose of investigational product and experienced any follow-up for safety. Treatment group was assigned based on the actual investigational product received.

Arm/Group Title	Monovalent Influenza Virus Vaccine	Placebo
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.	Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.
Measure Participants	240	60
Number [participants]	1 0.4%	1 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovalent Influenza Virus Vaccine, Placebo
	Comments	The percentage of subjects with fever was compared between the two treatment groups based on the upper limit of the two-sided 95% CIs for rate difference (monovalent vaccine minus placebo). The upper limit of the two-sided 95% CI was evaluated against the pre-specified equivalence criterion of 5 percentage points which corresponded to the following hypotheses: - H0 (null): rate difference ≥ 5 percentage points, - HA (alternative): rate difference < 5 percentage points.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on similar fever rate with 300 evaluable subjects (240 vaccine and 60 placebo recipients), the study would provide at least 98% power to rule out a rate increase of 5 percentage points assuming the true difference between the treatment groups is zero and the true fever rate is ≤ 1.0%. Power would be lower if the true difference was different from zero.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	rate difference
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -7.9 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Reporting Any Solicited Symptom or at Least One Adverse Event (AE)
Description	Solicited symptoms were collected from administration of investigational product through Study Day 15. For this study, solicited symptoms included: fever (> 100°F oral), runny nose, sore throat, cough, vomiting, muscle aches, chills, decreased activity (tiredness), headache.
Time Frame	Days 1-8 after vaccination

Outcome Measure Data

Analysis Population Description

The Safety Population includes all subjects who received at least one dose of investigational product and experienced any follow-up for safety. Treatment group was assigned based on the actual investigational product received.

Arm/Group Title	Monovalent Influenza Virus Vaccine	Placebo
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.	Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.
Measure Participants	240	60
Any solicited symptom	97 40.4%	23 38.3%
Fever > 100°F	2 0.8%	1 1.7%
Fever ≥ 101°F	1 0.4%	1 1.7%
Fever > 102°F	0 0%	0 0%
Fever > 103°F	0 0%	0 0%
Runny nose	66 27.5%	10 16.7%
Sore throat	33 13.8%	4 6.7%
Cough	10 4.2%	3 5%
Vomiting	1 0.4%	1 1.7%
Muscle aches	15 6.3%	4 6.7%
Chills	0 0%	0 0%
Decreased activity (tiredness)	18 7.5%	2 3.3%
Headache	42 17.5%	11 18.3%
Total participants reporting ≥ one AE	27 11.3%	2 3.3%

3. Secondary Outcome

Title	Number of Participants Reporting Any Solicited Symptom or at Least One AE
Time Frame	Days 1-15 after vaccination

Outcome Measure Data

Analysis Population Description

The Safety Population includes all subjects who received at least one dose of investigational product and experienced any follow-up for safety. Treatment group was assigned based on the actual investigational product received.

Arm/Group Title	Monovalent Influenza Virus Vaccine	Placebo
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.	Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.
Measure Participants	240	60
Any solicited symptom	102 42.5%	25 41.7%
Fever > 100°F	3 1.3%	1 1.7%
Fever ≥ 101°F	1 0.4%	1 1.7%
Fever > 102°F	0 0%	0 0%
Fever > 103°F	0 0%	0 0%
Runny nose	68 28.3%	11 18.3%
Sore throat	38 15.8%	4 6.7%
Cough	13 5.4%	3 5%
Vomiting	1 0.4%	1 1.7%
Muscle aches	16 6.7%	4 6.7%
Chills	1 0.4%	0 0%
Decreased activity (tiredness)	19 7.9%	2 3.3%
Headache	44 18.3%	13 21.7%
Total participants reporting ≥ one AE	29 12.1%	3 5%

4. Secondary Outcome

Title	Number of Participants Reporting at Least One Serious Adverse Event (SAE) or New Onset Chronic Disease (NOCD)
Description	SAEs were those that resulted in death; were life-threatening; resulted in inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; were a congenital anomaly/birth defect in the offspring of a study participant; or were an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed above. An NOCD was a newly diagnosed medical condition of a chronic, ongoing nature and assessed by the investigator as medically significant.
Time Frame	Days 1-29 after vaccination

Outcome Measure Data

Analysis Population Description

The Safety Population includes all subjects who received at least one dose of investigational product and experienced any follow-up for safety. Treatment group was assigned based on the actual investigational product received.

Arm/Group Title	Monovalent Influenza Virus Vaccine	Placebo
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.	Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.
Measure Participants	240	60
Total participants reporting ≥ one SAE	0 0%	0 0%
Total participants reporting ≥ one NOCD	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants Reporting at Least One Serious Adverse Event (SAE) or New Onset Chronic Disease (NOCD)
Description	SAEs were those that resulted in death; were life-threatening; resulted in inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability or incapacity; were a congenital anomaly/birth defect in the offspring of a study participant; or were an important medical event that may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed above. An NOCD was a newly diagnosed medical condition of a chronic, ongoing nature and assessed by the investigator as medically significant.
Time Frame	Days 1-181 after vaccination

Outcome Measure Data

Analysis Population Description

The Safety Population includes all subjects who received at least one dose of investigational product and experienced any follow-up for safety. Treatment group was assigned based on the actual investigational product received.

Arm/Group Title	Monovalent Influenza Virus Vaccine	Placebo
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.	Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.
Measure Participants	240	60
Total participants reporting ≥ one SAE	2 0.8%	0 0%
Total participants reporting ≥ one NOCD	0 0%	0 0%

Adverse Events

Time Frame	From the time that written informed consent was obtained, AEs were collected through Day 15 after vaccination and SAEs were collected through Day 181 after vaccination.
Arm/Group Title	Monovalent Influenza Virus Vaccine		Placebo
Arm/Group Description	Frozen monovalent vaccine containing the new strain was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer, egg allantoic fluid, and approximately 10^7 fluorescent focus units (FFU) of influenza virus type B/Brisbane/60/2008 (Victoria lineage). A single dose of investigational product was administered on Day 1.		Placebo was supplied in intranasal sprayers containing a total volume of 0.5 mL of sucrose-phosphate buffer and egg allantoic fluid. A single dose of investigational product was administered on Day 1.
All Cause Mortality
	Monovalent Influenza Virus Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Monovalent Influenza Virus Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/240 (0.8%)		0/60 (0%)
Endocrine disorders
Thyroid disorder	1/240 (0.4%)	1	0/60 (0%)	0
Hepatobiliary disorders
Gallbladder disorder	1/240 (0.4%)	1	0/60 (0%)	0
Infections and infestations
Clostridium difficile colitis	1/240 (0.4%)	1	0/60 (0%)	0
Other (Not Including Serious) Adverse Events
	Monovalent Influenza Virus Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/240 (9.6%)		3/60 (5%)
Gastrointestinal disorders
Nausea	2/240 (0.8%)	2	1/60 (1.7%)	1
Abdominal distension	0/240 (0%)	0	1/60 (1.7%)	1
Reproductive system and breast disorders
Menstruation irregular	0/240 (0%)	0	1/60 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Nasal congestion	17/240 (7.1%)	17	0/60 (0%)	0
Sneezing	4/240 (1.7%)	4	0/60 (0%)	0
Skin and subcutaneous tissue disorders
Cold sweat	0/240 (0%)	0	1/60 (1.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome. The PIs also agree for data to be presented first as a joint, multi-center publication.