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INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED)

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ClinicalTrials.gov Identifier: NCT02787044
Recruitment Status : Active, not recruiting
First Posted : June 1, 2016
Last Update Posted : October 9, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
University of Wisconsin, Madison
University of Toronto
Boston VA Research Institute, Inc.
Patient-Centered Outcomes Research Institute
Information provided by (Responsible Party):
Scott David Solomon, Brigham and Women's Hospital

Tracking Information
First Submitted Date  ICMJE May 25, 2016
First Posted Date  ICMJE June 1, 2016
Last Update Posted Date October 9, 2019
Study Start Date  ICMJE August 2016
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2016)
All-Cause Death or Cardiopulmonary Hospitalization [ Time Frame: Up to 3 years ]
Tme to first occurrence of death or cardiopulmonary hospitalization
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02787044 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2016)
  • Total cardiopulmonary hospitalizations or death [ Time Frame: Up to 3 years ]
    Total (first and recurrent) cardiopulmonary hospitalizations or death
  • Death or cardiopulmonary hospitalization within each influenza season [ Time Frame: Up to one year from randomization ]
    Time to first occurrence of cardiovascular death or cardiovascular hospitalization within each influenza season
  • Death or cardiopulmonary hospitalizations across all influenza seasons [ Time Frame: Up to three years ]
    Death or cardiopulmonary hospitalization across all enrolled influenza seasons
  • All-Cause Mortality [ Time Frame: Up to 3 years ]
    Time to first occurrence of all-cause mortality
  • Cardiopulmonary Hospitalization [ Time Frame: Up to 3 years ]
    Time to first occurrence of cardiopulmonary hospitalization
  • Number of participants with treatment-related adverse events [ Time Frame: Up to 3 years ]
    Number of participants with treatment-related adverse events
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure
Official Title  ICMJE INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure
Brief Summary INVESTED will test the hypothesis that high dose trivalent influenza vaccine will reduce cardiopulmonary events to a greater extent than standard dose quadrivalent influenza vaccine in high-risk cardiovascular patients with a recent history of myocardial infarction or heart failure. The trial will enroll 9300 participants over one Vanguard (pilot) season and three additional influenza seasons. The primary endpoint will be a composite of all-cause mortality or cardiopulmonary hospitalization.
Detailed Description

Influenza leads to significant morbidity and mortality, particularly in patients with cardiovascular disease. Influenza-related death is more common in patients with cardiovascular disease than any other chronic health condition. Influenza infection has been temporally associated with acute cardiovascular events, such as acute coronary syndrome and acute heart failure. Due to the increased risk for influenza-related complications, annual influenza immunization is recommended by the Centers for Disease Control and Prevention, (CDC) the American Heart Association, and the American College of Cardiology, and widespread influenza vaccination has been associated with reduced cardiac-related hospital admissions, acute exacerbations of heart failure, and winter mortality. Moreover, a meta-analysis has shown that annual vaccination reduces the risk for major adverse cardiovascular events (MACE) by 36%, with a more prominent effect in those with recent acute myocardial infarction (AMI).

Several lines of evidence suggest that a strategy of utilizing high-dose influenza vaccine in at risk cardiovascular patients would reduce morbidity and mortality. Immune responses to influenza vaccine, normally subject to variability by age and concomitant medical conditions, are substantially reduced in patients with heart failure evidenced by lower vaccine-induced antibody titers compared to healthy controls. In a randomized trial, antibody responses in patients with heart failure were augmented by using a higher dose of influenza vaccine. In a meta-analysis, higher dose influenza vaccination was associated with a 27% reduced risk for MACE compared to standard dose vaccine. A randomized study of high dose versus standard dose influenza vaccine in medically-stable patients over age 65 showed that participants receiving high dose vaccine had a 24% reduced risk of laboratory-confirmed influenza associated with protocol-defined influenza-like-illness, and had a low risk for adverse events. High dose influenza vaccine is FDA approved for use in medically stable adults over the age of 65, but has not been studied for patients under the age of 65 or in those with unstable, high risk medical conditions. The CDC does not preferentially recommend one influenza vaccine over another, and the optimal vaccine formulation that offers the most clinical protection in these high risk patients is unknown.

The high morbidity and health care costs among patients with high risk cardiovascular disease along with the reduced immune responses to standard dose influenza vaccines in patients with heart failure provides a compelling rationale to investigate alternative influenza vaccination strategies in this group. INVESTED is an outcomes study in patients with recent acute myocardial infarction (AMI) or heart failure (HF) to test whether a four-fold higher dose of trivalent influenza vaccine will reduce morbidity and mortality compared to standard dose quadrivalent vaccine. INVESTED will test the hypothesize that high dose vaccine will reduce the composite of all cause death or cardiopulmonary hospitalizations in this population, with the following specific aims:

Specific Aim 1. To test the hypothesis that high dose trivalent influenza vaccine will reduce the composite of death or cardiopulmonary events compared with standard dose quadrivalent influenza vaccine in high-risk cardiovascular patients. Patients with recent AMI or HF hospitalization will be randomized to high dose versus standard dose vaccine for up to three influenza seasons. The primary endpoint will be time to first occurrence of death or cardiopulmonary hospitalization within each influenza season. Hospitalizations will be ascertained utilizing multiple approaches (phone, patient report, and electronic health records). Key secondary outcome measures will include total (first and recurrent) cardiopulmonary hospitalizations or death, time to first occurrence of cardiovascular death or cardiopulmonary hospitalization, time to occurrence of all-cause death or cardiopulmonary hospitalization across all enrolled influenza seasons, time to occurrence of all-cause death, and time to first occurrence of cardiopulmonary hospitalizations.

Specific Aim 2. To test the hypothesis that antibody titers to influenza vaccine antigens are associated with cardiopulmonary outcomes. In a subset of participants, antibody titers by hemagglutination inhibition assays to influenza vaccine antigens at baseline and at 4 weeks following randomization will be determined, corresponding to achievement of maximal antibody titer levels after vaccination. The association between geometric mean titers post-vaccination and the occurrence of death or cardiopulmonary hospitalization (primary outcome measure of Specific Aim 1) will be assessed.

Other key correlative study (immune) outcome measures will include:

Change in antibody titers at 4 weeks post-vaccination from baseline to influenza vaccine antigens Seroconversion (demonstration of 4-fold rise in antibody concentrations from baseline) and seroprotection (demonstration of antibody titer level of 1:40) to A/H1N1, A/H3N2, and B-type vaccine antigens

The results of this trial have the potential to inform health care policy regarding optimal influenza vaccination for individuals with high risk cardiovascular disease, which may in turn reduce morbidity from this annual threat to health stability in patients with cardiovascular conditions.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Heart Failure
  • Myocardial Infarction
Intervention  ICMJE
  • Biological: High Dose Trivalent Influenza Vaccine
    High Dose Trivalent Influenza Vaccine
  • Biological: Standard Dose Quadrivalent Influenza Vaccine
    Standard Dose Quadrivalent Influenza Vaccine
Study Arms  ICMJE
  • Experimental: High Dose Influenza Vaccine
    High Dose Influenza Vaccine
    Intervention: Biological: High Dose Trivalent Influenza Vaccine
  • Active Comparator: Standard Dose Influenza Vaccine
    Standard Dose Influenza Vaccine
    Intervention: Biological: Standard Dose Quadrivalent Influenza Vaccine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 8, 2019)
5388
Original Estimated Enrollment  ICMJE
 (submitted: May 31, 2016)
9300
Estimated Study Completion Date  ICMJE February 2021
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • >= 18 years of age
  • history of hospitalization for myocardial infarction within 1 year of enrollment OR a history of hospitalization for heart failure within 2 years of enrollment
  • At least one of the following additional risk factors:

    • Prior MI (if HF the index event above; or a second MI)
    • Prior HF hospitalization (if MI the index event above; or a second HF event)
    • Age ≥ 65
    • LVEF < 40%
    • Diabetes mellitus
    • Obesity (BMI ≥ 30)
    • Renal impairment (eGFR ≤ 60)
    • History of ischemic stroke
    • History of peripheral artery disease
    • Current smoking

Exclusion Criteria:

  • Known allergy, hypersensitivity (anaphylaxis), or Guillain-Barré Syndrome within 6 weeks after influenza vaccine
  • Any non-cardiac condition that in the opinion of the investigator would lead to life expectancy less than 9 months.
  • Receipt of influenza vaccine during current influenza season
  • Any illness requiring treatment with antibiotics or anti-inflammatory medication within the past 14 days.
  • Any fever over 100 degrees Fahrenheit or 38 degrees Celsius within the past 7 days.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02787044
Other Study ID Numbers  ICMJE 2015P001823
U01HL130163 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be shared according to NIH data sharing rules
Responsible Party Scott David Solomon, Brigham and Women's Hospital
Study Sponsor  ICMJE Brigham and Women's Hospital
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • University of Wisconsin, Madison
  • University of Toronto
  • Boston VA Research Institute, Inc.
  • Patient-Centered Outcomes Research Institute
Investigators  ICMJE
Principal Investigator: Orly Vardeny, PharmD, MS University of Minnesota
Principal Investigator: Scott D Solomon, MD Brigham and Women's Hospital
Principal Investigator: KyungMann Kim, PhD University of Wisconsin, Madison
PRS Account Brigham and Women's Hospital
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP