Protocol Synopsis

INVESTED is a multi-center, randomized, double-blind, active-controlled clinical trial of high dose influenza vaccine compared to standard dose influenza vaccine for up to three seasons in adult individuals at high risk for cardiovascular events. The primary outcome is time to first occurrence of all-cause death or cardiopulmonary hospitalization per influenza season, and key secondary outcomes include total (first and recurrent) cardiopulmonary hospitalizations or death, time to first composite of cardiovascular death or cardiovascular hospitalization within each influenza season, and time to first composite of death or cardiopulmonary hospitalization across all enrolled influenza seasons.

You can read more about the INVESTED study design and rationale in our design paper here

STUDY HYPOTHESIS

 

We hypothesize that a higher dose of influenza vaccine is superior to standard influenza vaccine in reducing the risk of all-cause death or cardiopulmonary hospitalization among high-risk cardiovascular patients. 

 

STUDY OBJECTIVES

 

Primary Objective

 

The primary objective is to compare high dose influenza vaccine to standard dose vaccine in reducing the time to first composite of death or cardiopulmonary hospitalization within each influenza season. 

 

Secondary Objectives

 

  • To compare the effect of high dose influenza vaccine versus standard dose vaccine on total (first and recurrent) cardiopulmonary hospitalizations or death

  • To compare the effect of high dose influenza vaccine versus standard dose vaccine on time to first composite of cardiovascular death or cardiovascular hospitalization within each influenza season

  • To compare the effect of high dose influenza vaccine versus standard dose vaccine on time to first composite of death or cardiopulmonary hospitalization across all enrolled influenza seasons

  • To compare the effect of high dose influenza vaccine versus standard dose vaccine on the individual components of the primary endpoint

 

 

Secondary Objective: Analysis of immune efficacy in subgroup of 1000 participants

 

To test the hypothesis that a higher influenza vaccine dose will result in more pronounced humoral immune response, evidenced by greater mean titers post-vaccination and higher antibody titer changes from baseline, and to test the hypothesis that higher antibody concentrations will be associated with the reduced rate of the composite of all-cause death and cardiopulmonary hospitalization. Antibody titers to influenza vaccine antigens, seroprotection, and seroconversion will be assessed in a subgroup of participants (N=1,000)

 

 

STUDY DESIGN 

 

This is a multi-center, randomized, double-blind, active-controlled trial comparing two formulations of influenza vaccine in high risk cardiovascular patients (history of myocardial infarction or heart failure). Participants will be recruited from sites in the United States and Canada, over three influenza seasons. One group will receive standard dose quadrivalent, inactivated influenza vaccine (15 μg/strain, QIV), and the other group will receive a four-fold dose of trivalent, inactivated influenza vaccine (60 μg/strain, TIV).  Each season, the same vaccine will be administered according to each participant’s assigned randomized therapy.

 

STUDY POPULATION

 

The study population will consist of 9,300 adult patients without a previous history of intolerance to a standard dose of influenza vaccine. 

 

Inclusion Criteria

(1) Patients age ≥ 18 years with a history of a qualifying CV event:

  • Hospitalization for a spontaneous MI (within one year of enrollment); or

  • Hospitalization for heart failure (within two years of enrollment) 

      If heart failure: 

  • Must have diagnosis in medical records or ICD-9 code

  • Not currently acutely decompensated  

AND

(2) 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.

  • Participation in an investigational drug study. 

Intervention or Treatment: 

One group will receive a standard dose (15 μg per viral strain) of quadrivalent inactivated influenza vaccine, and the other group will receive a four-fold dose (60 μg per viral strain) of trivalent inactivated vaccine, administered once yearly for up to three influenza seasons. Patients will be randomized to a strategy at enrollment and maintained on that strategy in successive years.


Endpoints/ Outcomes:

 

Primary endpoint:

  • Time to first occurrence of all-cause death or cardiopulmonary hospitalization within each influenza season

Secondary endpoints: 

  • Total (first and recurrent) cardiopulmonary hospitalizations or death

  • Time to first composite of cardiovascular death or cardiovascular hospitalization within each influenza season

  • Time to first composite of death or cardiopulmonary hospitalization across all enrolled influenza seasons

  • Individual components of the primary endpoint, including time to all-cause mortality and time to first occurrence of cardiopulmonary hospitalization

Exploratory Endpoints: 

  • Time to first occurrence of all-cause death or cardiopulmonary hospitalization according to effectiveness of vaccine relative to virulence of influenza strain and the quality of the match between influenza strain and vaccine within individual seasons 

  • Time to first occurrence of cardiovascular death or heart failure hospitalization

  • Time to first occurrence of cardiovascular death, non-fatal MI, or non-fatal stroke 

  • Time to first occurrence of all-cause death and pulmonary hospitalizations

 

Safety endpoints:

  • Incidence of vaccine injection site reactions, vaccine-related adverse events and serious adverse events

 

Secondary Immune function endpoints in a subset of 1,000 participants

  • Geometric mean titers post-vaccination

  • Change in antibody titers at 4 weeks post-vaccination from baseline

  • Seroconversion, i.e. 4-fold rise in antibody concentrations from baseline to A/H1N1, A/H3N2, and B-type vaccine antigens

  • Seroprotection, i.e. antibody titer levels ≥ 1:40 to the A/H3N2, A/H1N1, and B-type vaccine antigens 4 weeks following influenza vaccination