Single Ascending Dose Challenge Study to Determine Safety and Reactogenicity of an Influenza Challenge Virus

Study Overview
=================
Brief Summary
-----------------
This is a non-controlled, open-label, single-center, dose-escalation study to determine the safety, infectivity, and immune responses elicited from of the potential influenza virus challenge strain. The study objective is to determine the dose with the optimal safety profile and infectivity rate of the viral challenge strain in healthy volunteers for use in subsequent challenge intervention studies to test potential influenza vaccines and/or therapeutics.

Official Title
-----------------
A Phase I, Open-label, Ascending Dose Study to Determine the Safety and Reactogenicity of a Wild Type Seasonal A/California/ H1N1 2009 Influenza Challenge Virus in Healthy Volunteers, Following a Single Intranasal Administration

Conditions
-----------------
Influenza

Intervention / Treatment
-----------------
* Biological: Live, wild-type A/California/H1N1 2009 influenza virus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy, as determined by medical history, physical examination, vital signs, echocardiogram, 12-lead ECG, and clinical safety laboratory examinations at baseline, as determined by the Investigator. Absent or low levels of detectable pre-existing antibodies to influenza virus subtypes, including as a minimum the challenge strain, as determined by an HAI titer of ≤10 prior to challenge. Non-smoker (no smoking within the last year and a history of less than 10 packs per year total) and agree to not use tobacco products during participation in the study. Female subjects of childbearing potential must: Not be breastfeeding Have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day -1 Will use oral, implantable, transdermal, or injectable contraceptives for 30 days prior to administration of the A/California/H1N1 2009 virus until the follow-up visit is performed. Use another reliable form of contraception approved by the Investigator (eg, intrauterine device, female condom, diaphragm with spermicide, cervical cap, use of condom by the sexual partner or a sterile sexual partner) from the time of screening until the follow-up visit is performed. Female subjects not of childbearing potential must: Be at least 1 year post-menopausal, or Be surgically sterile Male subjects able to father a child and sexually active with a female of childbearing potential, must agree to use a double barrier method of birth control (eg, condom with spermicidal foam, cream gel) and to not donate sperm during the study, from the day of enrollment until the Day 60 (±3) follow-up visit. If the female partner is using an effective method of contraception, a single barrier method of birth control for the male is acceptable. Comprehension of the study requirements, expressed availability for the required study period, and ability to be quarantined for up to 10 days and to attend the scheduled follow up visit. Negative alcohol and urine drug screening tests prior to entering quarantine. Being willing to adhere to the prohibitions and restrictions specified in this protocol Exclusion Criteria: Prior receipt of any influenza vaccine within the previous 2 years. Significant adulthood history of seasonal hay fever or a seasonal allergic rhinitis or perennial allergic rhinitis or chronic or nasal or sinus condition such as chronic sinusitis. Abnormal nasal structure including septal deviation and nasal polyps, or surgery to the nose or nasopharynx within 6 months of signing the informed consent form or recent (within the last 6 months) history of frequent or prolonged episodes of epistaxis. Suffering from asthma, bronchiectasis, emphysema, chronic obstructive pulmonary disease or any other chronic lung disease. A history of childhood asthma before the age of 12 is acceptable provided the subject is asymptomatic without treatment. Subjects with a single episode of wheezing after age 12 (lasting less than 8 weeks) can be included at the investigator's discretion. A female who is pregnant or who is breast feeding Diastolic BP, systolic BP or, pulse not consistent with normal vital signs, based on investigator judgment. Current use or use of intranasal corticosteroids within the last 30 days prior to the administration of the investigational virus product (Study Day 1). Presence of significant uncontrolled medical, neurological or psychiatric illness (acute or chronic) as assessed by the Investigator. This includes, but is not limited to, institution of new surgical or medical treatment for a chronic condition), or a significant dose alteration for uncontrolled symptoms or drug toxicity within 3 months of screening and reconfirmed on Day -1 prior to challenge. Positive serology for HIV-1 or HIV-2, or HBsAg or HCV antibodies. Cancer or treatment for cancer, within 5 years, excluding basal cell carcinoma of the skin, which is allowed. Presence of immunosuppression or any medical condition that may be associated with impaired immune responsiveness, including, but not limited to, diabetes mellitus inflammatory bowel disease. Presently receiving (or history of receiving) or during the preceding 3-month period prior to screening, any medications or other treatments that may adversely affect the immune system such as allergy injections, immune globulin, interferon, immunomodulators, cytotoxic drugs or other drugs known to be frequently associated with significant major organ toxicity, or systemic corticosteroids (oral or injectable) azathioprine or mercaptopurine. Topical corticosteroids except intranasal will be allowed. Use of intranasal corticosteroids within the last 30 days prior to the administration of the investigational virus product (Study Day 1) is prohibited. Chronic condition requiring prescription or over-the-counter medicine, with the exception of vitamins. Anticipated presence of a household contact with documented severe immunosuppression (as defined by CD4 < 200/mm³ or an absolute neutrophil count < 1500/mm³), either as a result of disease and/or therapy. Anticipated presence of a household contact aged ≤ 5 years, aged > 64 years, or a pregnant contact within 2 weeks following challenge. Current professional activity as a caregiver or healthcare worker who will return to work within 2 weeks following challenge. History of anaphylactic type reaction to egg or egg protein, adverse reaction to oseltamivir, a previous severe allergic reaction with generalized uticaria, angioedema, or anaphylaxis History of Guillain-Barre syndrome History of drug or chemical abuse in the year before the study. Receipt of any investigational virus product or nonregistered drug within the 30 days prior to challenge or currently enrolled in any investigational drug study or intends to enroll in such a study within the ensuing study period. Receipt of blood or blood products 6 months prior to challenge or planned administration during the study period. Blood donation in the last 26 weeks. Acute disease within 72 hours prior to challenge, defined as the presence of a moderate or severe illness with or without fever (as determined by the Investigator through medical history and physical examination), or presence of a fever ≥ 38ºC oral. Elevated white cell count above 10.5 x 109/L or an absolute neutrophil count above 7.5 x 109/L. Any condition that, in the opinion of the Investigator, might interfere with the primary study objective. Drinks more than 1200 mL (or 5 cups of 240 mL per cup) of tea/coffee/cocoa/cola or other caffeinated beverage per day more than one day per week in the 2 weeks before screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>1:10 dilution of neat virus (0.25mL of 1:10 dilution per nostril of neat virus; approximate quantity 3.5 x 10^6TCID50/dose) | Biological: Live, wild-type A/California/H1N1 2009 influenza virus<br>* Live, wild type influenza A virus that was inoculated and manufactured in allantoic fluid of SPF embryonated hen eggs<br>|
| Experimental: Cohort 2<br>1:5 dilution of neat virus (0.25mL of 1:5 dilution per nostril of neat virus; approximate quantity 7 x 10^6TCID50/dose) | Biological: Live, wild-type A/California/H1N1 2009 influenza virus<br>* Live, wild type influenza A virus that was inoculated and manufactured in allantoic fluid of SPF embryonated hen eggs<br>|
| Experimental: Cohort 3<br>1:10 dilution of neat virus (0.5mL of 1:10 dilution per nostril of neat virus; approximate quantity 7 x 10^6TCID50/dose) | Biological: Live, wild-type A/California/H1N1 2009 influenza virus<br>* Live, wild type influenza A virus that was inoculated and manufactured in allantoic fluid of SPF embryonated hen eggs<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral Shedding | Number of participants with viral shedding, assessed from nasopharyngeal swabs using RT-PCR and cell culture assay | Day 9 | 
| Seroconversion | Greater than or equal to 4-fold rise in HAI titer by study Day 60 relative to baseline | Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Severity of AEs | The number of AEs in each Cohort rated as mild, moderate, or severe intensity | Day 60 |