A Phase II Study in Healthy Adults 19 Years and Older to Assess the Safety, Reactogenicity and Immunogenicity of a Sanofi Pasteur A/H7N9 Inactivated Influenza Vaccine Administered Intramuscularly With or Without AS03 Adjuvant
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 720
- 试验地点
- 5
- 主要终点
- Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies
研究概览
简要总结
This is a randomized, double-blinded, Phase II study in healthy males and non-pregnant females 19 years and older that is designed to assess the safety, reactogenicity, and immunogenicity of a pre-pandemic 2017 monovalent inactivated influenza A/H7N9 virus vaccine (2017 H7N9 IIV) administered at different dosages given with AS03 adjuvant and phosphate buffered saline (PBS) diluent, with AS03 adjuvant only, and without adjuvant. Eligible subjects will be randomized into 5 study groups, stratified by age. The study will enroll up to 420 individuals 19-64 years old and up to 300 individuals who are 65 years old and older. Study duration is approximately 16 months with subject participation duration approximately 13 months. The primary objectives of this study are: 1) to assess the safety and reactogenicity following receipt of two doses of 2017 H7N9 IIV administered intramuscularly at different dosages approximately 21 days apart given with or without AS03 adjuvant; 2) to assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody responses following receipt of two doses of 2017 H7N9 IIV administered intramuscularly at different dosages approximately 21 days apart with or without AS03 adjuvant, stratified by age of recipient.
详细描述
This is a randomized, double-blinded, Phase II study in healthy males and non-pregnant females 19 years and older. This clinical trial is designed to assess the safety, reactogenicity, and immunogenicity of a pre-pandemic 2017 monovalent inactivated influenza A/H7N9 virus vaccine (2017 H7N9 IIV) administered at different dosages given with or without adjuvant. 3.75 mcg of HA per dose will be administered with phosphate buffered saline (PBS) diluent and AS03 adjuvant, 7.5 mcg and 15 mcg of HA per dose will be administered with AS03 adjuvant only, and 15 mcg and 45 mcg of HA per dose will be administered without adjuvant. Eligible subjects will be randomized into one of 5 study groups, stratified by age. The study will enroll up to 420 individuals 19-64 years old and up to 300 individuals who are 65 years old and older. The study duration is approximately 16 months with subject participation duration approximately 13 months. The primary objectives of this study are: 1) to assess the safety and reactogenicity following receipt of two doses of 2017 H7N9 IIV administered intramuscularly at different dosages approximately 21 days apart given with or without AS03 adjuvant; 2) to assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody responses following receipt of two doses of 2017 H7N9 IIV administered intramuscularly at different dosages approximately 21 days apart with or without AS03 adjuvant, stratified by age of recipient. The secondary objectives are: 1) to assess unsolicited non-serious adverse events (AEs) following receipt of two doses of a 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without AS03 adjuvant; 2) to assess medically-attended adverse events (MAAEs) including new-onset chronic medical conditions (NOCMCs), potentially immune-mediated medical conditions (PIMMCs), and all serious adverse events (SAEs) following receipt of two doses of a 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without AS03 adjuvant; 3) to assess the serum HAI and Neut antibody responses approximately 7 and 21 days following receipt of a single dose, and approximately 7 days following receipt of two doses of 2017 H7N9 IIV administered IM at different dosages approximately 21 days apart with or without AS03 adjuvant, stratified by age of recipient.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 19 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Provide written informed consent prior to initiation of any study procedures.
- •Are able to understand and comply with planned study procedures and be available for all study visits.
- •Are males or non-pregnant females, 19 years of age and older, inclusive.
- •Are in good health*. *As determined by medical history and physical examination to evaluate acute or currently ongoing chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions should be stable for the last 60 days (no hospitalizations, ER, or urgent care for condition and no adverse symptoms that need medical intervention such as medication change/supplemental oxygen). This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the site principal investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and study vaccination are acceptable provided there was no deterioration in the subject's chronic medical condition that necessitated a medication change, and there is no additional risk to the subject or interference with the evaluation of responses to study vaccination. Note: Topical, nasal, and inhaled medications (with the exception of inhaled corticosteroids as outlined in the Subject Exclusion Criteria), herbals, vitamins, and supplements are permitted.
- •Oral temperature is less than 100.0 degrees Fahrenheit.
- •Pulse is 47 to 100 bpm, inclusive.
- •Systolic blood pressure is 85 to 150 mmHg, inclusive (subjects <65 years of age), 85 to 160 mmHg, inclusive (subjects = / > 65 years of age).
- •Diastolic blood pressure is 55 to 95 mmHg, inclusive.
- •Erythrocyte sedimentation rate (ESR) is less than 30 mm per hour.
- •Women of childbearing potential* must use an acceptable contraception method** from 30 days before first study vaccination until 60 days after last study vaccination.
- •*Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or <1 year of the last menses if menopausal.
- •**Acceptable contraception includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving the first study vaccination, barrier methods such as condoms or diaphragms with spermicide or foam, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill").
- •Women of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to study vaccination.
排除标准
- •Have an acute illness*, as determined by the site principal investigator or appropriate sub-investigator, within 72 hours prior to study vaccination.
- •*An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site principal investigator or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.
- •Have any medical disease or condition that, in the opinion of the site principal investigator or appropriate sub-investigator, is a contraindication to study participation*.
- •*Including acute or chronic medical disease or condition, defined as persisting for at least 90 days, that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this trial.
- •Have immunosuppression as a result of an underlying illness or treatment, a recent history or current use of immunosuppressive or immunomodulating disease therapy.
- •Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 3 years prior to study vaccination.
- •Have known active neoplastic disease or a history of any hematologic malignancy. Non-melanoma, treated, skin cancers are permitted.
- •Have known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection.
- •Have known hypersensitivity or allergy to eggs, egg or chicken protein, squalene-based adjuvants, or other components of the study vaccine.
- •Have a history of severe reactions following previous immunization with licensed or unlicensed influenza vaccines.
- •Have a personal or family history of narcolepsy.
- •Have a history of Guillain-Barré syndrome.
- •Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination.
- •Have a history of Potentially Immune-Mediated Medical Conditions (PIMMCs).
- •Have a history of alcohol or drug abuse within 5 years prior to study vaccination.
- •Have any diagnosis, current or past, of schizophrenia, bipolar disease, or other psychiatric diagnosis that may interfere with subject compliance or safety evaluations.
- •Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 10 years prior to study vaccination.
- •Have taken oral or parenteral (including intra-articular) corticosteroids of any dose within 30 days prior to study vaccination.
- •Have taken high-dose inhaled corticosteroids* within 30 days prior to each study vaccination.
- •*High-dose defined as per age as using inhaled high dose per reference chart https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/quick-reference-html#estimated-comparative-daily-doses
- •Received a licensed live vaccine within 30 days prior to the first study vaccination, or plan to receive a licensed live vaccine within 30 days before or after each study vaccination.
- •Received or plan to receive a licensed, inactivated, vaccine (excluding all flu vaccines) within 14 days before or after each study vaccination.
- •Received or plan to receive an inactivated seasonal flu vaccine within 21 days before or after each study vaccination.
- •Received immunoglobulin or other blood products (with exception of Rho D immunoglobulin) within 90 days prior to each study vaccination.
- •Received an experimental agent* within 30 days prior to the first study vaccination, or expect to receive an experimental agent** during the 13-month trial-reporting period.
- •*Including vaccine, drug, biologic, device, blood product, or medication.
- •**Other than from participation in this trial.
- •Are participating or plan to participate in another clinical trial with an interventional agent* that will be received during the 13-month trial-reporting period.
- •*Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication.
- •Received or plan to receive an influenza A/H7 vaccine* or have a history of influenza A/H7 subtype infection.
- •*And assigned to a group receiving influenza A/H7 vaccine, does not apply to documented placebo recipients.
- •Have traveled to mainland China and had substantial* direct contact with live or freshly slaughtered poultry or pigeons within the past five years.
- •*Substantial contact is defined as visited a poultry farm and/or a live poultry market.
- •Occupational exposure to or substantial direct physical contact* with birds in the past year and through the 21 days after the second study vaccination.
- •*Exposure to free range chickens in the yard is exclusionary. Casual contact with birds at petting zoos or county or state fairs or having pet birds does not exclude subjects from study participation.
- •Female subjects who are breastfeeding or plan to breastfeed at any given time from the first study vaccination until 30 days after the last study vaccination.
- •Plan to travel outside the US (continental US, Hawaii, and Alaska) from enrollment through 21 days after the second study vaccination.
研究组 & 干预措施
Group 3
15 mcg of H7N9 vaccine plus AS03 adjuvant on days 1 and 22, n=100 (19-64 years old) and n=60 (65 and older)
干预措施: Inactivated influenza H7N9 vaccine (Biological)
Group 1
3.75 mcg of H7N9 vaccine with PBS diluent plus AS03 adjuvant on days 1 and 22, n=100 (19-64 years old) and n=60 (65 and older)
干预措施: AS03 (Drug)
Group 1
3.75 mcg of H7N9 vaccine with PBS diluent plus AS03 adjuvant on days 1 and 22, n=100 (19-64 years old) and n=60 (65 and older)
干预措施: Inactivated influenza H7N9 vaccine (Biological)
Group 1
3.75 mcg of H7N9 vaccine with PBS diluent plus AS03 adjuvant on days 1 and 22, n=100 (19-64 years old) and n=60 (65 and older)
干预措施: Phosphate Buffered Saline (PBS) diluent (Other)
Group 2
7.5 mcg of H7N9 vaccine plus AS03 adjuvant on days 1 and 22, n=100 (19-64 years old) and n=60 (65 and older)
干预措施: AS03 (Drug)
Group 2
7.5 mcg of H7N9 vaccine plus AS03 adjuvant on days 1 and 22, n=100 (19-64 years old) and n=60 (65 and older)
干预措施: Inactivated influenza H7N9 vaccine (Biological)
Group 3
15 mcg of H7N9 vaccine plus AS03 adjuvant on days 1 and 22, n=100 (19-64 years old) and n=60 (65 and older)
干预措施: AS03 (Drug)
Group 4
15 mcg of unadjuvanted H7N9 vaccine on days 1 and 22, n=50 (19-64 years old) and n=30 (65 and older)
干预措施: Inactivated influenza H7N9 vaccine (Biological)
Group 5
45 mcg of unadjuvanted H7N9 vaccine on days 1 and 22, n=50 (19-64 years old) and n=30 (65 and older)
干预措施: Inactivated influenza H7N9 vaccine (Biological)
结局指标
主要结局
Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies
时间窗: Day 43
Blood was collected for HAI assay which was conducted with the 2017 H7N9 vaccine virus as the antigen. Each sample was tested at least twice per the laboratory's standard operating procedure, and the geometric mean of the replicate results was calculated as that sample's result. The geometric mean titer was calculated for each study arm from the available results at 21 days after the second dose of H7N9.
Percentage of Participants Achieving Seroconversion Defined by Hemagglutination Inhibition (HAI) Antibodies
时间窗: Day 43
Blood was collected for the HAI assay conducted with the 2017 H7N9 vaccine virus as the antigen. Each sample was tested at least twice per the laboratory's standard operating procedure, and the geometric mean of the replicate results was calculated as that sample's result. Seroconversion was defined as HAI pre-vaccination titer \<1:10 and post-vaccination titer \>=1:40 or pre-vaccination titer 1:10 or greater and minimum 4-fold rise in post-vaccination antibody titer. 21 days after second dose of H7N9 is Day 43.
Geometric Mean Titers (GMTs) of Serum Neutralizing (Neut) Antibodies
时间窗: Day 43
Blood was collected for Neutralizing assay which was conducted with the 2017 H7N9 vaccine virus as the antigen. Each sample was tested at least twice per the laboratory's standard operating procedure, and the geometric mean of the replicate results was calculated as that sample's result. The geometric mean titer was calculated for each study arm from the available results at 21 days after the second dose of H7N9.
Number of Participants With Clinical Safety Laboratory Adverse Events
时间窗: Day 29
Laboratory parameters include alanine aminotransferase (ALT), bilirubin, creatinine, hemoglobin, platelets and white blood cells (WBC). Thresholds for adverse events were considered as ALT 44 IU/L or greater (female) or 61 IU/L or greater (male); bilirubin 1.30 mg/dL or greater; creatinine 1.1 mg/dL or greater (female) or 1.4 mg/dL or greater (male); hemoglobin 11.4 g/dL or lower (female) or 12.4 g/dL or lower (male); platelets 139 x10\^3/µL or below or 416 x10\^3/µL or greater; or WBC or 3.9 x10\^3/µL or lower or 10.6 x10\^3/µL or higher.
Number of Participants Reporting Solicited Injection Site Events
时间窗: Day 22 to Day 29
Injection site AEs solicited on a memory aid provided to participants included Pain, Tenderness, Itching/Pruritus, Ecchymosis/Bruising (functional grade based on interference with dailyactivities), Ecchymosis/Bruising (any measured value \>0mm), Erythema/Redness (functional grade), Erythema/ Redness (any measured value \>0mm), Induration/Swelling (functional grade), and Induration/Swelling (any measured value \>0mm). Participants are considered reporting the injection site AE if they reported mild or greater severity at any time during the 8 days at or following the second vaccination.
Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibodies Titer of 1:40 or Greater
时间窗: Day 43
Blood was collected for the HAI assay conducted with the 2017 H7N9 vaccine virus as the antigen. Each sample was tested at least twice per the laboratory's standard operating procedure, and the geometric mean of the replicate results was calculated as that sample's result. The percentage of participants with HAI titer \>= 1:40 was calculated for each study group from the available results at 21 days after second dose of H7N9.
Percentage of Participants Achieving Neutralizing (Neut) Antibodies Titer of 1:40 or Greater
时间窗: Day 43
Blood was collected for the Neutralizing assay conducted with the 2017 H7N9 vaccine virus as the antigen. Each sample was tested at least twice per the laboratory's standard operating procedure, and the geometric mean of the replicate results was calculated as that sample's result. The percentage of participants with Neut titer \>= 1:40 was calculated for each study group from the available results at 21 days after second dose of H7N9.
Number of Participants Reporting Study Vaccine-related Serious Adverse Events (SAEs)
时间窗: Day 1 to Day 387
SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. Events are included if deemed by the investigator to be related to the study product.
Number of Participants Reporting Systemic Reactogenicity Events
时间窗: Day 22 to Day 29
Systemic AEs solicited on a memory aid provided to participants included Elevated Oral Temperature, Feverishness, Fatigue, Malaise, Myalgia, Arthralgia, Headache, and Nausea. Participants are considered reporting the systemic AE if they reported mild or greater severity at any time during the 8 days at or following the second vaccination.
Percentage of Participants Achieving Seroconversion Defined by Neutralizing (Neut) Antibodies
时间窗: Day 43
Blood was collected for the Neutralizing assay conducted with the 2017 H7N9 vaccine virus as the antigen. Each sample was tested at least twice per the laboratory's standard operating procedure, and the geometric mean of the replicate results was calculated as that sample's result. Seroconversion was defined as Neut pre-vaccination titer \<1:10 and post-vaccination titer \>=1:40 or pre-vaccination titer 1:10 or greater and minimum 4-fold rise in post-vaccination antibody titer. 21 days after second dose of H7N9 is Day 43.
次要结局
- Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies(Day 29)
- Number of Participants Reporting Study Vaccine-related Unsolicited Non-serious Adverse Events (AEs)(Day 1 to Day 43)
- Number of Participants Reporting Serious Adverse Events (SAEs), Regardless of the Assessment of Relatedness(Day 1 to Day 387)
- Number of Participants Reporting Medically-attended Adverse Events (MAAEs), New-onset Chronic Medical Conditions (NOCMCs), and Potentially Immune-mediated Medical Conditions (PIMMCs)(Day 1 to Day 387)
- Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibodies Titers of 1:40 or Greater(Day 29)
- Percentage of Participants Achieving Seroconversion Defined by Neutralizing (Neut) Antibodies(Day 29)
- Percentage of Participants Achieving Seroconversion Defined by Hemagglutination Inhibition (HAI) Antibodies(Day 29)
- Number of Participants Reporting Unsolicited Adverse Events (AEs), Regardless of the Assessment of Seriousness or Relatedness(Day 1 to Day 43)
- Percentage of Participants Achieving Neutralizing (Neut) Antibodies Titers of 1:40 or Greater(Day 29)
- Geometric Mean Titers (GMTs) of Serum Neutralizing (Neut) Antibodies(Day 29)