TIV and High Dose TIV in Subjects With Rheumatoid Arthritis
TIV and High Dose TIV in Subjects With Rheumatoid Arthritis
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.
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.
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.