Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid arthritis, Flu vaccine, Influenza
Brief summary
Patients with rheumatoid arthritis have increased risk of seasonal influenza and influenza-related complications but have reduced vaccine immunogenicity. It is unknown whether patients with rheumatoid arthritis would benefit from more immunogenic vaccine formulations. This study investigated the immunogenicity and safety of a high-dose trivalent inactivated influenza vaccine (HD-TIV) in patients with rheumatoid arthritis compared to a standard-dose quadrivalent influenza vaccine (SD-QIV).
Detailed description
Influenza, a vaccine-preventable respiratory disease, is ranked 8th among the causes of death in the Canadian population. Among rheumatoid arthritis (RA) patients, the incidence of both seasonal influenza and serious influenza-related illness (IRI) are increased. Despite being a high priority group targeted for vaccination, the diagnosis of RA and other patient-specific factors (i.e. older age, treatment, current smoking) are linked to impaired vaccination responses. Thus the burden of influenza among people with RA is disproportionally high, and interventions to improve responses to influenza vaccination are urgently needed. Strategies to optimize protection in another vulnerable group, the elderly, include the use of quadrivalent vaccines, higher antigen doses, and adjuvants. A high-dose, trivalent, inactivated influenza vaccine (HD-TIV) has recently been shown to have a similar safety profile to standard dose vaccine (SD-TIV) with improved immunogenicity and protection in adults ≥65 years of age. Whether or not analogous strategies to improve responses to influenza vaccine will enhance protection in people with RA is unknown. The investigators hypothesize that the use of the HD-influenza vaccine will improve vaccine-induced protection (i.e. seroconversion and seroprotection) in people with RA compared to SD-influenza vaccine. The investigators propose to conduct a stratified, randomized, modified double blind, active-controlled trial to assess immune responses to two commercial influenza vaccines containing different antigen doses in individuals with RA.
Interventions
BIOLOGICALHD-TIV
BIOLOGICALSD-QIV
Sponsors
The Arthritis Society, Canada
McGill University Health Centre/Research Institute of the McGill University Health Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of seropositive RA (rheumatoid factor (RF) and/or anti-CCP antibody positive) based on the 2010 ACR-EULAR criteria. 2. At least 6 months of treatment including anti-TNF agents, abatacept, rituximab (dose received within the previous 6 months) and/or methotrexate. 3. Informed consent form signed and dated. 4. Able to attend all scheduled visits and to comply with all trial procedures.
Exclusion criteria
1. Vaccination against influenza in the 6 months preceding the trial vaccination. 2. Systemic hypersensitivity to eggs, chicken proteins, or any of the vaccine components, or a history of a life-threatening reaction to TIV or to a vaccine containing any of the same substances. 3. History of Guillain-Barré syndrome within six weeks of a previous influenza vaccination. 4. Dementia or any other cognitive condition that could interfere with the trial procedures. 5. Thrombocytopenia or bleeding disorder contraindicating IM vaccination (according to treating rheumatologist). 6. Current alcohol abuse or drug addiction. 7. Moderate or severe acute illness with or without fever. If this exists, vaccination will be deferred until the individual has been medically stable and/or afebrile for at least 24 hours. 8. Signs and symptoms of an acute infectious respiratory illness. If this exists, vaccination will be deferred until the symptoms resolve. 9. Pregnant women (the rationale for excluding this group is not their lack of indication for vaccination but the changes of maternal immune responses during pregnancy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seroprotection Rate to HD- Versus SD-IV in People With RA | Day 28 | Seroprotection rate (SPR): the proportion of subjects in a given treatment group attaining a reciprocal HI titre of ≥1:40 at D28 post-vaccination. |
| Seroconversion Rate to HD- Versus SD-IV in People With RA | Day 28 | Seroconversion rate (SCR): proportion of subjects in a given treatment group (SD- or HD) with either a ≥4-fold increase in reciprocal HI titres between D0 and D28 or a rise of undetectable HI titre (i.e. \<1:10) pre-vaccination (D0) to an HI titre of ≥1:40 at D28 post vaccination. |
| Geometric Mean Titres (GMTs) of HI in People With RA Who Received HD- Versus SD-IV | Day 28 | Geometric mean titres (GMTs) of HI at D28. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Side Effects During the Surveillance Period in SD- and HD-IV. | Day 28 | Number of Participants with Side Effects |
| Durability of Detectable Levels of HI Antibody for SD- and HD- IV. | Day 186 | Number of participants with detectable HI antibodies at Day 186 |
Other
| Measure | Time frame |
|---|---|
| Performance of the Micro-neutralization Assay in Comparison to the HI Assay. | Day 186 |
| Rates of Health Care Use in Patients Receiving SD- or HD-IV. | Day 186 |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Dose Influenza Vaccine Patients will receive one dose of FLUZONE® Standard Dose Quadrivalent Inactivated Influenza Vaccine (SD-QIV)
SD-QIV | 136 |
| High Dose Influenza Vaccine Patients will receive one dose of FLUZONE® High Dose Trivalent Inactivated Influenza Vaccine (HD-TIV)
HD-TIV | 138 |
| Total | 274 |
Baseline characteristics
| Characteristic | Standard Dose Influenza Vaccine | High Dose Influenza Vaccine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 59 Participants | 53 Participants | 112 Participants |
| Age, Categorical Between 18 and 65 years | 77 Participants | 85 Participants | 162 Participants |
| Age, Continuous | 61.9 years STANDARD_DEVIATION 11.8 | 59.7 years STANDARD_DEVIATION 13.9 | 60.8 years STANDARD_DEVIATION 12.85 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants | 13 Participants | 27 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 6 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 9 Participants | 18 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 106 Participants | 110 Participants | 216 Participants |
| Sex: Female, Male Female | 109 Participants | 109 Participants | 218 Participants |
| Sex: Female, Male Male | 27 Participants | 29 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 136 | 2 / 138 |
| other Total, other adverse events | 14 / 136 | 19 / 138 |
| serious Total, serious adverse events | 0 / 136 | 0 / 138 |
Outcome results
Primary
Geometric Mean Titres (GMTs) of HI in People With RA Who Received HD- Versus SD-IV
Geometric mean titres (GMTs) of HI at D28.
Time frame: Day 28
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Standard Dose Influenza Vaccine | Geometric Mean Titres (GMTs) of HI in People With RA Who Received HD- Versus SD-IV | 1.56 titer |
| High Dose Influenza Vaccine | Geometric Mean Titres (GMTs) of HI in People With RA Who Received HD- Versus SD-IV | 2.06 titer |
Primary
Seroconversion Rate to HD- Versus SD-IV in People With RA
Seroconversion rate (SCR): proportion of subjects in a given treatment group (SD- or HD) with either a ≥4-fold increase in reciprocal HI titres between D0 and D28 or a rise of undetectable HI titre (i.e. \<1:10) pre-vaccination (D0) to an HI titre of ≥1:40 at D28 post vaccination.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Dose Influenza Vaccine | Seroconversion Rate to HD- Versus SD-IV in People With RA | 12 Participants |
| High Dose Influenza Vaccine | Seroconversion Rate to HD- Versus SD-IV in People With RA | 31 Participants |
Primary
Seroprotection Rate to HD- Versus SD-IV in People With RA
Seroprotection rate (SPR): the proportion of subjects in a given treatment group attaining a reciprocal HI titre of ≥1:40 at D28 post-vaccination.
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Dose Influenza Vaccine | Seroprotection Rate to HD- Versus SD-IV in People With RA | 42 Participants |
| High Dose Influenza Vaccine | Seroprotection Rate to HD- Versus SD-IV in People With RA | 67 Participants |
Secondary
Durability of Detectable Levels of HI Antibody for SD- and HD- IV.
Number of participants with detectable HI antibodies at Day 186
Time frame: Day 186
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Dose Influenza Vaccine | Durability of Detectable Levels of HI Antibody for SD- and HD- IV. | 29 Participants |
| High Dose Influenza Vaccine | Durability of Detectable Levels of HI Antibody for SD- and HD- IV. | 43 Participants |
Secondary
Rates of Side Effects During the Surveillance Period in SD- and HD-IV.
Number of Participants with Side Effects
Time frame: Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Dose Influenza Vaccine | Rates of Side Effects During the Surveillance Period in SD- and HD-IV. | 19 Participants |
| High Dose Influenza Vaccine | Rates of Side Effects During the Surveillance Period in SD- and HD-IV. | 20 Participants |
Other Pre-specified
Performance of the Micro-neutralization Assay in Comparison to the HI Assay.
Time frame: Day 186
Other Pre-specified
Rates of Health Care Use in Patients Receiving SD- or HD-IV.
Time frame: Day 186