TIV and High Dose TIV in Subjects With Rheumatoid Arthritis

Study Overview
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Brief Summary
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A randomized, double-blinded, Phase II study in adults with Rheumatoid Arthritis receiving TNF-alpha-inhibitor therapy aged 18 to 64 years of age and healthy gender-and age-matched control subjects . This study will investigate the immunogenicity, safety, and reactogenicity of two different doses of inactivated trivalent influenza virus vaccine (Sanofi Pasteur Fluzone [15 mcg x 3 strains] and Sanofi Pasteur Fluzone High Dose [60 mcg x 3 strains]) administered intramuscularly in individuals with rheumatoid arthritis receiving anti-TNF-alpha (TNFi) therapy and healthy age- and gender- matched controls.

Detailed Description
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This is a randomized, double-blinded, Phase II study in adults with Rheumatoid Arthritis receiving TNF-alpha inhibitor therapy, aged 18 years to 64 years of age. This study is designed to investigate the immunogenicity, safety, and reactogenicity of two different doses of inactivated trivalent influenza virus vaccine given at two dose levels (15 mcg and 60 mcg) administered IM in individuals with rheumatoid arthritis receiving anti-TNF-alpha therapy or age and gender matched control subjects. The study is conducted over two seasons, 2011-2012 and 2012-2013. Subjects enrolling between October 2011 and February 2012 will receive the 2011-2012 vaccine, while those enrolling after July 2012 will receive the 2012-2013 vaccine. Immunogenicity testing will determine the proportion of subjects in each group with titer a 4-fold rise in HAI titers (defined as either a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer >/=1:40 or a pre-vaccination HAI titer >/=1:10 and a minimum four-fold rise in post-vaccination HAI titer) against each of the specific influenza strains included in vaccine the subject received at day 21 following vaccination. The proportion of subjects in each group achieving a serum HAI titer of >/= 1:40 or a 4-fold rise in HAI titer or greater in HAI titer against each strain in the vaccine compared to the controls subjects. Safety testing will assess the occurrence of vaccine-associated Serious adverse events (SAEs) throughout the course of the study, and the occurrence of solicited local and systemic adverse events (AEs) within 8 days post vaccination. Solicited AEs (including rheumatoid arthritis clinical status) will be assessed during the course of the study. Subjects will have four face to face visits and one telephone contact. Day 0 will include the consent process, a medical history and physical exam for the RA subjects to assess the activity of their RA at the time of enrollment, vital signs, phlebotomy for prevaccine serology. Subjects will be randomized to receive IM seasonal TIV or High-Dose TIV at this visit and will receive the assigned vaccine. They will be observed for 20 minutes and will be taught to fill out a 7 day memory aid that will assess daily temperature, local and systemic reactogenicity. A telephone call will be made to assess reactogenicity and to review the memory aid on day 3. Subjects will return on day 7 for review of the memory aid, AEs/SAEs, vital signs and phlebotomy for serology. A physical exam will be performed if indicated. They will return on day 21 and at 6 months for review of AEs/SAEs, vital signs and phlebotomy for serology. A physical exam will be performed if indicated.

Official Title
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A Phase II Study in Adults With Rheumatoid Arthritis Receiving TNF-alpha-inhibitor Therapy to Assess the Immunogenicity and Safety of Trivalent Inactivated Vaccine (TIV) and High Dose Trivalent Inactivated Vaccine (High-Dose TIV) Administered at Two Dosage Levels

Conditions
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Influenza

Intervention / Treatment
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* Biological: Trivalent inactivated influenza vaccine
* Biological: Trivalent inactivated influenza vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria for RA Subjects Male or non-pregnant female between the ages of 18 and 64 years, inclusive, who has stable RA and has received TNFi therapy during the previous 3 months. Female subjects: for the 30 days prior to enrollment through 30 days following receipt of TIV or HTIV vaccine must fulfill one of the following: (i) she is not able to bear children because she has been surgically sterilized (tubal ligation or hysterectomy) for at least one year or is at least 1 year post-menopausal or (ii) she agrees to practice effective methods of contraception including, but not limited to, abstinence, barrier methods (such as a condom or diaphragm) used with a spermicide, birth control pills, patches or hormonal shots or hormonal implants, NuvaRing and IUDs (intrauterine devices). Adherence to contraceptive method will be captured on the appropriate case report form (CRF). In good health, as determined by vital signs (see toxicity table in section 9.2.1.1), medical history to ensure any existing medical diagnoses or conditions are stable and not considered clinically significant, and physical examination. Intend to be available through 6 months following receipt of vaccine. Able to understand and comply with planned study procedures. Provide written informed consent prior to initiation of any study procedures. Inclusion Criteria for Healthy Subjects Male or non-pregnant female between the ages of 18 and 64 years, inclusive. Female subjects: for the 30 days prior to enrollment through 30 days following receipt of TIV or HTIV vaccine must fulfill one of the following: (i) she is not able to bear children because she has been surgically sterilized (tubal ligation or hysterectomy) for at least one year or is at least 1 year post-menopausal or (ii) she agrees to practice effective methods of contraception including, but not limited to, abstinence, barrier methods (such as a condom or diaphragm) used with a spermicide, birth control pills, patches or hormonal shots or hormonal implants, NuvaRing and IUDs (intrauterine devices). Adherence to contraceptive method will be captured on the appropriate case report form (CRF). In good health, as determined by vital signs (see toxicity table in section 9.2.1.1), medical history to ensure any existing medical diagnoses or conditions are stable and not considered clinically significant, and physical examination. Intend to be available through 6 months following receipt of vaccine. Able to understand and comply with planned study procedures. Provide written informed consent prior to initiation of any study procedures. Exclusion Criteria: Exclusion Criteria for all Subjects For subjects enrolled after July 2012: Enrolled in this study during the 2011-2012 flu season. Has received the seasonal influenza vaccine for the current season. For subjects enrolling between October 2011 and February 2012, this is the 2011-2012 seasonal influenza vaccine. For subjects enrolling after July 2012, this is the 2012-2013 seasonal influenza vaccine. Has a known allergy to eggs, egg proteins or other components in the vaccines (i.e. formaldehyde, gelatin sodium phosphate, sodium chloride, octylphenol ethoxylate). Has a known or suspected latex allergy or sensitivity. Has a positive urine or serum pregnancy test within 24 hours prior to vaccination (if female of childbearing potential as defined in Inclusion criterion 2), or women who are breastfeeding. Has a history of severe reactions following immunization with contemporary influenza virus vaccines. Has an active neoplastic disease or a history of any hematologic malignancy (cancers of blood or bone marrow) or current bleeding or blood clotting disorder. For healthy volunteer (without RA) subjects: Long term (at least 14 days of prednisone 2 mg/kg or equivalent other glucocorticoid) use of oral, parenteral or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months. (Nasal and topical steroids are allowed.) Has a diagnosis of a current and uncontrolled major psychiatric disorder. Has been hospitalized in the past 10 years for psychiatric illness, suicide attempt, or confinement for danger to self or others. Is receiving listed psychiatric drugs as below*. Subjects who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment, without decompensating are allowed enrollment into the study. * aripiprazole, clozapine, ziprasidone, haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, chlorprothixene, chlorpromazine, perphenazine, trifluopromazine, olanzapine, carbamazepine, divalproex sodium, lithium carbonate, lithium citrate, lamotrigine, prochlorperazine, paliperidone or iloperidone. Has a history of receiving immunoglobulin or other blood product within the 3 months prior to vaccination in this study. Has received an experimental/investigational agent (vaccine, drug, biologic, device, blood product, or medication) within 28 days prior to vaccination in this study, or expects to receive an experimental/investigational agent within the study time period (180 days after vaccination in this study). Is participating or plans to participate in another clinical trial with a licensed product during the 6-month study period. Has received any other licensed vaccines within 14 days (for inactivated vaccines) or 21 days (for live vaccines) prior to vaccination in this study, or expects to receive a licensed vaccine during the 21 days after vaccination in this study. Has received antiviral agent against influenza A and/or B within 48 hours prior to vaccination in this study. Antiviral agents should not be administered until 2 weeks after vaccination in this study unless medically necessary. Has an acute or chronic medical condition other than RA that, in the opinion of the investigator, would interfere with the evaluation of responses (this includes, but is not limited to: known chronic liver, lung or heart disease, chronic anemia, (non-RA subjects only), metabolic disorders such as diabetes (resolved gestational diabetes is acceptable), significant renal disease, transplant recipients, system lupus erythematosus, psoriatic arthritis or gout). Has a moderate to severe acute illness and/or an oral temperature greater than or equal to 100.4 degrees Fahrenheit, within 72 hours prior to vaccination. (This may result in a temporary delay of vaccination). Immunosuppression as a result of an underlying illness or treatment other than RA therapy, or use of anti-cancer chemotherapy or radiation therapy within the preceding 36 months. Known infection with HIV, Hepatitis B or Hepatitis C infection or autoimmune hepatitis. Has a history of alcohol or drug abuse in the last 5 years. Has a history of Guillain-Barré Syndrome. Has any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk or render the subject unable to meet the requirements of the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 Controls<br>40 (up to 50) adults, healthy gender and age-matched controls, given a single 15 mcg intramuscular dose of Sanofi Pasteur Fluzone® | Biological: Trivalent inactivated influenza vaccine<br>* Inactivated trivalent influenza virus vaccine (Sanofi Pasteur Fluzone® [15 mcg x 3 strains]), as a single intramuscular dose. 80 and up to 100 subjects. Subjects enrolling between October 2011 and February 2012 will receive the 2011-2012 vaccine and subjects enrolling after July 2012 will receive the 2012-2013 vaccine.<br>|
| Experimental: Group 2<br>40 (up to 50) adults with Rheumatoid Arthritis receiving TNF-alpha-inhibitor therapy, given a single 60 mcg intramuscular dose of Sanofi Pasteur Fluzone® High Dose. | Biological: Trivalent inactivated influenza vaccine<br>* Inactivated trivalent influenza virus vaccine (Sanofi Pasteur Fluzone® High Dose [60 mcg x 3 strains]), as a single intramuscular dose. 80 and up to 100 subjects. Subjects enrolling between October 2011 and February 2012 will receive the 2011-2012 vaccine and subjects enrolling after July 2012 will receive the 2012-2013 vaccine.<br>|
| Experimental: Group 2 Controls<br>40 (up to 50) adults, healthy gender and age-matched controls, given a single 60 mcg intramuscular dose of Sanofi Pasteur Fluzone® High Dose. | Biological: Trivalent inactivated influenza vaccine<br>* Inactivated trivalent influenza virus vaccine (Sanofi Pasteur Fluzone® High Dose [60 mcg x 3 strains]), as a single intramuscular dose. 80 and up to 100 subjects. Subjects enrolling between October 2011 and February 2012 will receive the 2011-2012 vaccine and subjects enrolling after July 2012 will receive the 2012-2013 vaccine.<br>|
| Experimental: Group 1<br>40 (up to 50) adults with Rheumatoid Arthritis receiving TNF-alpha-inhibitor therapy, given a single 15 mcg intramuscular dose of Sanofi Pasteur Fluzone® | Biological: Trivalent inactivated influenza vaccine<br>* Inactivated trivalent influenza virus vaccine (Sanofi Pasteur Fluzone® [15 mcg x 3 strains]), as a single intramuscular dose. 80 and up to 100 subjects. Subjects enrolling between October 2011 and February 2012 will receive the 2011-2012 vaccine and subjects enrolling after July 2012 will receive the 2012-2013 vaccine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of RA Participants in the 2012-2013 Season Who Achieved Seroconversion at Day 21 Against Each of the 3 Specific Influenza Strains in Vaccine the Participant Received | Blood was collected from RA participants prior to vaccination and at the 21 day follow up visit for testing in the HAI assay with 2012-2013 seasonal influenza vaccine strains virus as the assay antigens. A participant met the threshold of seroconversion if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 titer was an increase by 4-fold or more. | Day 0 prior to and Day 21 following immunization | 
| Number of RA Participants in the 2011-2012 Season Who Achieved Seroconversion at Day 21 Against Each of the 3 Specific Influenza Strains in Vaccine the Participant Received | Blood was collected from RA participants prior to vaccination and at the 21 day follow up visit for testing in the HAI assay with 2011-2012 seasonal influenza vaccine strains virus as the assay antigens. A participant met the threshold of seroconversion if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 titer was an increase by 4-fold or more. | Day 0 prior to and Day 21 following immunization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting Solicited Systemic Symptoms Based on a Functional Grading Scale | Participants maintained a memory aid to record daily the occurrence of systemic symptoms of feverishness, malaise, myalgia, headache, nausea, chills, arthralgia, shivering, and asthenia for 8 days after vaccination (Day 0-7) based on their interference with daily activities, with a severity grade of mild meaning no interference, moderate as some interference and severe as significant interference/prevented daily activity. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days. | Day 0 to Day 7 | 
| Number of Participants Reporting Fever | Participants were provided with a thermometer and a memory aid on which to record daily oral temperatures for 8 days after vaccination (Day 0-7). The protocol defined fever as oral temperature of 38.0 degrees Celsius or higher. Participants are counted as experiencing fever if they reported oral temperatures of 38.0 degrees Celsius or higher on any of the 8 days. | Day 0 to Day 7 | 
| Number of Participants Reporting Solicited Local Injection Site Reactions Based on a Functional Grading Scale | Participants maintained a memory aid to record daily the occurrence of local injection site reactions of pain, tenderness, redness, and swelling for 8 days after vaccination (Day 0-7) based on their interference with daily activities, with a severity grade of mild meaning no interference, moderate as some interference and severe as significant interference/prevented daily activity. Participants are counted if they reported experiencing the symptom at any severity on any of the 8 days. | Day 0 to Day 7 | 
| Number of Participants Reporting Solicited Quantitative Local Injection Site Reactions | Participants maintained a memory aid to record daily the occurrence of local reactions of redness and swelling for 8 days after vaccination (Day 0-7). If the reaction was present, the maximum diameter was measured in millimeters (mm). Participants are counted if they reported experiencing the reaction with any measurement greater than 0 mm on any of the 8 days. | Day 0 to Day 7 | 
| Number of RA Participants in the 2011-2012 Season Who Achieved Seroconversion at Days 7 and 180 Against Each of the 3 Specific Influenza Strains in Vaccine the Participant Received | Blood was collected from RA participants prior to vaccination and at the Days 7 and 180 follow up visits for testing in the HAI assay with 2011-2012 seasonal influenza vaccine strains virus as the assay antigens. A participant met the threshold of seroconversion if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 titer was an increase by 4-fold or more. | Day 0 prior to and Days 7 and 180 following immunization | 
| Number of RA Participants in the 2012-2013 Season Who Achieved Seroconversion at Days 7 and 180 Against Each of the 3 Specific Influenza Strains in Vaccine the Participant Received | Blood was collected from RA participants prior to vaccination and at the Days 7 and 180 follow up visits for testing in the HAI assay with 2012-2013 seasonal influenza vaccine strains virus as the assay antigens. A participant met the threshold of seroconversion if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 titer was an increase by 4-fold or more. | Day 0 prior to and Days 7 and 180 following immunization | 
| Number of RA Participants With a Worsening Rheumatoid Arthritis Status During the Course of the Study, Based on the RAPID3 Score From the NP2 Questionnaire | The RAPID 3 score is an index of the three patient-reported measures from the Multi-Dimensional Health Assessment Questionnaire (MDHAQ) R808 and serves as an assessment of patient status for those with rheumatoid arthritis. The score consists of the cumulative total of the Function (FN), Pain (PN), and Patient Global (PTGL) values. The severity of the RAPID 3 score is categorized as: >12=High Severity; 6.1-12=Moderate Severity; 3.1-6=Low Severity; and ≤3=Remission. The NP2 questionnaire was completed by RA participants at all clinic visits. Scores at Days 7, 21 and 180 were compared to Day 0 to determine worsening, defined as moving from the baseline category to a more severe category. | Day 0 to Days 7, 21 and 180 | 
| Number of Participants in the 2011-2012 Season Who Achieved Seroconversion at Days 7, 21 and 180 Against Each of the 3 Specific Influenza Strains in Vaccine the Participant Received | Blood was collected from all participants prior to vaccination and at the Days 7, 21 and 180 follow up visits for testing in the HAI assay with 2011-2012 seasonal influenza vaccine strains virus as the assay antigens. A participant met the threshold of seroconversion if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 titer was an increase by 4-fold or more. | Day 0 prior to and Days 7, 21 and 180 following immunization | 
| Number of Participants in the 2012-2013 Season Who Achieved Seroconversion at Days 7, 21 and 180 Against Each of the 3 Specific Influenza Strains in Vaccine the Participant Received | Blood was collected from all participants prior to vaccination and at the Days 7, 21 and 180 follow up visits for testing in the HAI assay with 2012-2013 seasonal influenza vaccine strains virus as the assay antigens. A participant met the threshold of seroconversion if the Day 0 titer was less than 1:10 (the assay's lowest level of detection) and the Day 21 titer was 1:40 or greater, or the Day 0 titer was greater than or equal to 1:10 and the Day 21 titer was an increase by 4-fold or more. | Day 0 prior to and Days 7, 21 and 180 following immunization | 
| Number of Participants Reporting Vaccine-related Serious Adverse Events (SAEs) Throughout the Course of the Study. | Serious adverse events included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required in-patient hospitalization or prolongation thereof; resulted in a congenital anomaly/birth defect; or may have jeopardized the participant or required intervention to prevent one of these outcomes. Association to vaccination was determined by a study clinician licensed to make medical diagnosis. | Day 0 to Day 180 | 
| Geometric Mean Titers (GMT) for Each of the Specific Influenza Strains Included in Vaccine Received by Participants in the 2011-2012 Season | Blood was collected for HAI assay at Day 0 prior to vaccination and again at 7, 21 and 180 days following vaccination. The HAI assay was conducted with the three antigens in the 2011-2012 seasonal inactivated TIV. Within each 2011-2012 study arm, geometric mean titers and 95% confidence intervals were calculated for each antigen separately. | Days 0, 7, 21 and 180 | 
| Geometric Mean Titers (GMT) for Each of the Specific Influenza Strains Included in Vaccine Received by Participants in the 2012-2013 Season | Blood was collected for HAI assay at Day 0 prior to vaccination and again at 7, 21 and 180 days following vaccination. The HAI assay was conducted with the three antigens in the 2012-2013 seasonal inactivated TIV. Within each 2012-2013 study arm, geometric mean titers and 95% confidence intervals were calculated for each antigen separately. | Days 0, 7, 21 and 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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influenza, rheumatoid arthritis, TNF-alpha-inhibitor, Fluzone®, Fluzone® High Dose