A Single Ascending Dose Study in Adults (Stage 1) and Single Ascending Dose-Finding Study (Stage 2) in Elderly Subjects With ASP3772, A Pneumococcal Vaccine

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety, tolerability, and immunogenicity of 3 different dose levels of ASP3772 in comparison to the active comparator Prevnar 13® (PCV13) in adults 18 to 64 years of age in Stage 1. Stage 2 will evaluate the safety, tolerability, and immunogenicity of 3 different dose levels of ASP3772 in comparison to the active comparator PCV13 in elderly 65 to 85 years of age. In addition, Stage 2 will evaluate the immunogenicity of 3 different dose levels of ASP3772 relative to the response seen following administration of Pneumovax® 23 (PPSV23) for the serotypes not included in PCV13.

Detailed Description
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The study population will consist of 3 different groups: Group 1 - Stage 1 PCV13 naïve participants randomized within 3 sequential cohorts to ASP3772 or PCV13; Group 2 - Stage 2 PCV13 naïve participants randomized within 3 sequential cohorts to ASP3772 or PCV13; and Group 3 - Stage 2 participants previously vaccinated with PCV13 that will receive PPSV23.

Official Title
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A Phase 1/2, Randomized, Single Ascending Dose Study in Adults (Stage 1) and Randomized, Single Ascending Dose-Finding Study (Stage 2) in Elderly Subjects With ASP3772, a Pneumococcal Vaccine

Conditions
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Pneumonia, Bacterial, Healthy Volunteers, Pneumococcal Disease

Intervention / Treatment
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* Biological: ASP3772
* Biological: PCV13
* Biological: PPSV23


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage 1: Subject is healthy male or female between 18 and 64 year of age inclusive, at screening. Stage 2: Subject is a male or female between 65 and 85 years of age, inclusive, at screening who is healthy or has chronic controlled, stable disease with no change in disease severity, medical therapy and no hospitalization records in last 12 weeks as determined by medical history, physical examination and laboratory data. A female subject is eligible to participate if not pregnant and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR WOCBP who agrees to follow the contraceptive guidance at screening and for at least 28 days after the study vaccine administration. Female subject must agree not to breastfeed starting at screening and for 28 days after the study vaccine administration. Female subject must not donate ova starting at screening and for 28 days after the study vaccine administration. A male subject with female partner(s) of childbearing potential must agree to use contraception at screening and for at least 28 days after the study vaccine administration. Male subject must not donate sperm starting at screening and for 90 days after the study vaccine administration. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding at screening and for 28 after the study vaccine administration. Subject agrees not to participate in another interventional study while participating in the present study. Exclusion Criteria: Subject has a known or suspected hypersensitivity to ASP3772, its comparators or any components of the formulations used. Subject has had previous exposure with ASP3772. Subject has had known previous exposure with PPSV23. Subject has received PCV13 or any other licensed or investigational pneumococcal vaccine at any time. (Note: This exclusion criterion is not applicable to Group 3; those subjects 65 to 85 years of age who previously received immunization with PCV13. Prior PCV13 immunization should have taken place no less than 10 months and no more than 2 years prior to study vaccine administration. These subjects are eligible to be enrolled in the nonrandomized arm of Stage 2, Group 3. Subject has a history of microbiologically-proven invasive disease caused by S. pneumoniae. Subject has an immune disorder(s) (including autoimmune disease) and/or clinical conditions requiring immunosuppressive drugs. Subject has any evidence of any unstable or active clinically significant cardiovascular, gastrointestinal, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal and/or other major disease or malignancy, e.g., uncontrolled hypertension, uncontrolled diabetes, heart failure, uncontrolled chronic obstructive pulmonary disease, end-stage renal disease. Subject has history of illicit drug(s) or alcohol abuse that will interfere with the protocol requirements and/or a positive urine drug test (for Stage 1 subjects only) at screening. Subject has any clinically significant history of allergic conditions including drug allergies, asthma or anaphylactic reactions, but excluding untreated asymptomatic seasonal allergies prior to study vaccine administration. Subject has a coagulation disorder contraindicating intramuscular immunization. Subject has a positive serology test for hepatitis B surface antigen (HBsAg), hepatitis A virus antibodies (immunoglobulin M), hepatitis C virus antibodies (anti-HCV) confirmed by reflex testing (HCV-RNA) or antibodies to human immunodeficiency virus (HIV) type 1 and/or type 2 at screening. Subject has/had febrile illness (> 100.4°F oral equivalent) or symptomatic, viral, bacterial (including upper respiratory infection) or fungal (noncutaneous) infection within 1 week prior to day 1. Subject has any clinically significant abnormality from the physical examination, ECG and clinical laboratory tests during screening. Subject is unlikely to adhere to study procedures, keep appointments, is planning to relocate during the study or cannot be adequately followed for safety according to the protocol. Subject has any other condition, which precludes the subject's participation in the study. Subject has received any vaccines within 30 days prior of receipt of the study vaccine (exception: Influenza virus vaccine given according to recommended guidelines must be given at least 7 days prior to receiving study vaccine). Subject has had significant blood loss, donated 1 unit (450 mL or more) or received transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to day 1. Subject has received any systemically absorbed antibiotics during the 7-day period prior to day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1, Group 1 Adults, ASP3772 Low dose<br>Healthy adults aged 18 to 64 years received a low dose [1 microgram (μg)] of ASP3772 intramuscularly on Day 1. | Biological: ASP3772<br>* Participants received a single dose of ASP3772 (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose) intramuscularly<br>|
| Experimental: Stage 1, Group 1 Adults, ASP3772 Medium dose<br>Healthy adults aged 18 to 64 years received a medium dose (2 μg) of ASP3772 intramuscularly on Day 1. | Biological: ASP3772<br>* Participants received a single dose of ASP3772 (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose) intramuscularly<br>|
| Experimental: Stage 1, Group 1 Adults, ASP3772 High dose<br>Healthy adults aged 18 to 64 years received a high dose (5 μg) of ASP3772 intramuscularly on Day 1. | Biological: ASP3772<br>* Participants received a single dose of ASP3772 (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose) intramuscularly<br>|
| Active Comparator: Stage 1, Group 1, PCV13 Pooled Comparator<br>Healthy adults aged 18 to 64 years received a single dose of PCV13 0.5 milliliter (mL) intramuscularly on Day 1. Data from participants in each group given PCV13 were pooled for comparison with each ASP3772 dose group (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose). | Biological: PCV13<br>* Participants received a single dose of PCV13 intramuscularly.<br>* Other names: Prevnar 13;|
| Experimental: Stage 2, Group 2 Older Adults, ASP3772 Low dose<br>Healthy older adults aged 65 to 85 years received a low dose (1 μg) of ASP3772 intramuscularly on Day 1. | Biological: ASP3772<br>* Participants received a single dose of ASP3772 (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose) intramuscularly<br>|
| Experimental: Stage 2, Group 2 Older Adults, ASP3772 Medium dose<br>Healthy older adults aged 65 to 85 years received a medium dose (2 μg) of ASP3772 intramuscularly on Day 1. | Biological: ASP3772<br>* Participants received a single dose of ASP3772 (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose) intramuscularly<br>|
| Experimental: Stage 2, Group 2 Older Adults, ASP3772 High dose<br>Healthy older adults aged 65 to 85 years received a high dose (5 μg) of ASP3772 intramuscularly on Day 1. | Biological: ASP3772<br>* Participants received a single dose of ASP3772 (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose) intramuscularly<br>|
| Active Comparator: Stage 2, Group 2, PCV13 Pooled Comparator<br>Older adults aged 65 to 85 years received a single dose of PCV13 0.5 mL intramuscularly on Day 1. Data from participants in each group given PCV13 were pooled for comparison with each ASP3772 dose group (ASP3772 low dose, ASP3772 medium dose and ASP3772 high dose). | Biological: PCV13<br>* Participants received a single dose of PCV13 intramuscularly.<br>* Other names: Prevnar 13;|
| Active Comparator: Stage 2, Group 3, PPSV23 Comparator<br>Older adults aged 65 to 85 years who had been previously vaccinated with PCV13, were enrolled and received a single of dose PPSV23 on Day 1. | Biological: PPSV23<br>* Participants received a single dose of PPSV23 intramuscularly.<br>* Other names: Pneumovax 23;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), [Stage 1, Group 1] | An AE is any untoward medical occurrence in a participant administered a study vaccine, and which does not necessarily have to have a causal relationship with this vaccination. A TEAE is defined as any AE with onset within 30 days from study vaccine administration. Medically attended TEAEs (MAAEs) are AEs for which the participant has received medical attention by medical personnel, or in an emergency room, or which led to hospitalization. A new-onset chronic disease TEAEs (NOCD) is defined as a MAAE which a) was absent at baseline; b) has not resolved at the follow-up telephone call; c) requires continuous medical care or attention. Potentially Immune Mediated medical condition TEAEs (PIMMCs) are defined as any AEs of autoimmune or auto inflammatory nature. | From Day 1, Up to Day 180 | 
| Number of Participants With TEAEs, [Stage 2, Group 2] | An AE is any untoward medical occurrence in a participant administered a study vaccine, and which does not necessarily have to have a causal relationship with this vaccination. A TEAE is defined as any AE with onset within 30 days from study vaccine administration. Medically attended TEAEs (MAAEs) are AEs for which the participant has received medical attention by medical personnel, or in an emergency room, or which led to hospitalization. A new-onset chronic disease TEAEs (NOCD) is defined as a MAAE which a) was absent at baseline; b) has not resolved at the follow-up telephone call; c) requires continuous medical care or attention. Potentially Immune Mediated medical condition TEAEs (PIMMCs) are defined as any AEs of autoimmune or auto inflammatory nature. As specified in protocol, data was planned to be analyzed for PCV13 pooled comparator from each group given PCV13 to compare with each ASP3772 dose. | From Day 1, Up to Day 180 | 
| Number of Participants With TEAEs, [Stage 2, Group 3] | An AE is any untoward medical occurrence in a participant administered a study vaccine, and which does not necessarily have to have a causal relationship with this vaccination. A TEAE is defined as any AE with onset within 30 days from study vaccine administration. Medically attended TEAEs (MAAEs) are AEs for which the participant has received medical attention by medical personnel, or in an emergency room, or which led to hospitalization. A new-onset chronic disease TEAEs (NOCD) is defined as a MAAE which a) was absent at baseline; b) has not resolved at the follow-up telephone call; c) requires continuous medical care or attention. Potentially Immune Mediated medical condition TEAEs (PIMMCs) are defined as any AEs of autoimmune or auto inflammatory nature. | From Day 1, Up to Day 30 | 
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital signs parameters included blood pressure (hypotension and hypertension), pulse rate (tachycardia and bradycardia), body temperature and respiratory rate. Any change in vital sign abnormalities that was clinically significant in the medical and scientific judgment of the investigator and not related to an underlying disease was reported as an unsolicited adverse event (AE). Any clinically significant abnormality associated with underlying disease does not require reporting as an (S)AE unless judged by the investigator to be more severe than expected for the participant's condition. | During first hour post vaccination (vaccine administered at Day 1) | 
| Number of Participants With Potentially Clinically Significant Laboratory Values | Clinical laboratory testing included hematology, clinical chemistry, or urinalysis. Any abnormal laboratory test result (e.g., in hematology, clinical chemistry, or urinalysis) that was clinically significant in the medical and scientific judgment of the investigator and not related to an underlying disease was reported as an unsolicited adverse event (AE). Laboratory tests of clinical interest included total bilirubin ≥ 2x ULN and Alkaline phosphatase > 1.5 × upper limit of normal. Study Investigator's interest was to assess only potentially clinically significant values. | Up to Day 30 | 
| Number of Participants With Potentially Clinically Significant Physical Examination Values | A physical examination consists of an examination of general appearance, eyes, nose throat, neck (including thyroid), lymph nodes, chest, lungs, cardiovascular, abdomen, skin, extremities, musculoskeletal and neurological system including mental status. Any abnormal test result that was clinically significant in the medical and scientific judgment of the investigator and not related to an underlying disease was reported as an unsolicited adverse event (AE). Study Investigator's interest was to assess only potentially clinically significant values. | Up to Day 30 | 
| Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG), [Stage 1, Group 1] and [Stage 2, Group 2] | The Investigator assessed standard 12-lead ECG recordings for the purposes of safety assessment and participant management. Any clinically significant abnormality, as determined by the investigator's medical and scientific judgment and unrelated to underlying disease, should be reported as an unsolicited (S)AE. Any clinically significant abnormality associated with underlying disease does not require reporting as an (S)AE unless judged by the investigator to be more severe than expected for the participant's condition. | Day - 28 to Day -1 (28 days prior to study vaccination) | 
| Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG), [Stage 1, Group 1] and [Stage 2, Group 2] | The Investigator assessed standard 12-lead ECG recordings for the purposes of safety assessment and participant management. Any clinically significant abnormality, as determined by the investigator's medical and scientific judgment and unrelated to underlying disease, should be reported as an unsolicited (S)AE. Any clinically significant abnormality associated with underlying disease does not require reporting as an (S)AE unless judged by the investigator to be more severe than expected for the participant's condition. | At Day 7 | 
| Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG), [Stage 2, Group 3] | The Investigator assessed standard 12-lead ECG recordings for the purposes of safety assessment and participant management. Any clinically significant abnormality, as determined by the investigator's medical and scientific judgment and unrelated to underlying disease, should be reported as an unsolicited (S)AE. Any clinically significant abnormality associated with underlying disease does not require reporting as an (S)AE unless judged by the investigator to be more severe than expected for the participant's condition. | Day - 28 to Day -1 (28 days prior to study vaccination) | 
| Reactogenicity Assessed by Number of Participants With Solicited Local Reactions, [Stage 1, Group 1] | Local reactions include pain, tenderness, redness/erythema, swelling and induration. | Up to 7 Day post Vaccination (vaccine administered at Day 1) | 
| Reactogenicity Assessed by Number of Solicited Local Reactions, [Stage 2, Group 2 and Group 3] | Assessed solicited local reactions were pain, tenderness, redness/erythema, swelling, induration, itching at injection site and pruritus at injection site. | Up to 7 Day post Vaccination (vaccine administered at Day 1) | 
| Reactogenicity Assessed by Number of Solicited Systemic Reactions, [Stage 1, Group 1] | Assessed systemic reactions were nausea/vomiting, diarrhea, headache, fever, fatigue and muscle discomfort or pain/myalgia. | Up to 7 Day post Vaccination (vaccine administered at Day 1) | 
| Reactogenicity Assessed by Number of Solicited Systemic Reactions [Stage 2, Group 2 and Group 3] | Assessed systemic reactions were nausea/vomiting, diarrhea, headache, fever, fatigue and muscle discomfort or pain/myalgia. | Up to 7 Day post Vaccination (vaccine administered at Day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMTs) for Serotype-specific Opsonophagocytic Activity (OPA) Titer, [Stage 1, Group 1] | OPA titers were determined for serotypes: 1, 3,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F. OPA titer was expressed as the reciprocal of the serum dilution that causes a 50% reduction in the colony-forming units. | At Day 1 and Day 30 | 
| Geometric Mean Concentration (GMCs) for Serotype-specific Immunoglobulin G (IgG), [Stage 1, Group 1] | Immunological responses were assessed in terms of IgG GMCs and expressed as titers. The assessed serotypes were: 1, 3,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F. | At Day 1 and Day 30 | 
| Geometric Mean Fold Rise (GMFR) for Unique Serotypes IgG [Stage 1, Group 1] | Immunological responses were assessed in terms of IgG GMFRs. The assessed serotypes were: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, and 33F. | At Day 30 | 
| Percentage of Participants With Unique Serotypes IgG of Greater Than or Equal to (>=) 4-fold Increase, [Stage 1, Group 1] | Immunological responses were assessed in terms of percentage of participants with serotype-specific IgG concentration >=4-fold increase. The assessed serotypes were: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, 33F. | At Day 30 | 
| GMTs for Unique Serotype OPA Titer, [Stage 1, Group 1] | Immunological responses were assessed in terms of OPA GMTs. The assessed serotypes were: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, 33F. | At Day 30 | 
| GMTs for Serotype-specific OPA Titer, [Stage 2, Group 2] | Immunological responses were assessed in terms of OPA GMTs and expressed as titers. The assessed serotypes were: 1, 3,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F. | At Day 1 and Day 30 | 
| GMCs for Serotype-specific IgG, [Stage 2, Group 2] | Immunological responses were assessed in terms of IgG GMCs and expressed as titers. The assessed serotypes were: 1, 3,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F. | At Day 1 and Day 30 | 
| GMFR for Unique Serotypes IgG, [Stage 2, Group 2] | Immunological responses were assessed in terms of IgG GMFRs. The assessed serotypes were: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, and 33F. | At Day 30 | 
| Percentage of Participants With Unique Serotype-specific IgG Concentration of Greater Than or Equal to (>=) 4-fold Increase, [Stage 2, Group 2] | Immunological responses were assessed in terms of percentage of participants with unique serotypes IgG concentration >=4-fold increase. The assessed serotypes were: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, 33F. | At Day 30 | 
| Dose Response in OPA Titer for ASP3772 (Stage 2, Group 2) | An analysis of covariance (ANCOVA) model was conducted with age categories (65 to 74 years and 75 to 85 years) serving as covariates, and treatment groups (ASP3772 1 µg, 2 µg, and 5 µg) as the factor of interest. The natural logarithm (log) of pneumococcal OPA titers for each serotype were examined to assess the dose-response relationship. The assessed serotypes were: 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F,20B, 22F, 23F, and 33F. he assessed serotypes were: 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F,20B, 22F, 23F, and 33F. | At Day 30 | 
| Dose Response in the IgG Concentrations for ASP3772 [Stage 2, Group 2] | An analysis of covariance (ANCOVA) model was conducted with age categories (65 to 74 years and 75 to 85 years) serving as covariates, and treatment groups (ASP3772 1 µg, 2 µg, and 5 µg) as the factor of interest. The natural logarithm (log) of IgG concentrations for each serotype were examined to assess the dose-response relationship. | At Day 30 | 
| GMTs for Unique Serotype OPA Titer [Stage 2, Group 2 and Group 3] | Immunological responses were assessed in terms of OPA GMTs. The assessed serotypes were: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, 33F. | At Day 30 | 
| GMCs for Unique Serotypes IgG, [Stage 2, Group 2 and Group 3] | Immunogenicity was measured in terms of IgG GMCs and expressed as titers. The assessed serotypes were: 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, 33F. | At Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pneumococcal vaccine, Vaccine, Pneumococccal Disease, ASP3772