A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Adults at Increased Risk for Pneumococcal Disease (V114-017/PNEU-DAY)

Study Overview
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Brief Summary
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This study is designed to 1) describe the safety, tolerability, and immunogenicity of V114 and Prevnar 13™ in pneumococcal vaccine-naïve adults at increased risk for pneumococcal disease and to 2) describe the safety, tolerability, and immunogenicity of PNEUMOVAX™23 when administered 6 months after receipt of either V114 or Prevnar 13™. Increased risk for pneumococcal disease is defined as 1) an underlying medical condition, 2) behavioral habits such as smoking or alcohol use, or 3) living in a community/environment with increased risk of disease transmission.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by Administration of PNEUMOVAX™23 Six Months Later in Immunocompetent Adults Between 18 and 49 Years of Age at Increased Risk for Pneumococcal Disease (PNEU - DAY)

Conditions
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Pneumococcal Infections

Intervention / Treatment
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* Biological: V114
* Biological: Prevnar 13™
* Biological: PNEUMOVAX™23


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Native American participant enrolled from any of the clinical sites of the Johns Hopkins Center for American Indian Health (CAIH) without any of the pre-specified risk conditions for pneumococcal disease listed below, OR Native American participant enrolled from any of the CAIH sites or participant from a site other than CAIH with ≥1 of the following risk conditions for pneumococcal disease: Diabetes mellitus Type 1 or Type 2 and with hemoglobin A1c (HgA1c) <10% Chronic liver disease with documented history of compensated cirrhosis (Child-Pugh Score A) Confirmed diagnosis of Chronic Obstructive Pulmonary Disease (COPD) with spirometric Global Initiative for Chronic Obstructive Lung Disease Stage 1 to 3 Confirmed diagnosis of mild or moderate persistent asthma receiving guideline directed therapy Confirmed diagnosis of chronic heart disease (New York Heart Association [NYHA] heart failure Class 1 to 3, receiving guideline-directed oral heart failure treatment) due to reduced or preserved ejection fraction or due to non-cyanotic congenital heart disease. Current smoker Female participant: not pregnant, not breastfeeding and 1) not of childbearing potential, or 2) of childbearing potential and agrees to practice contraception through 6 weeks after last administration of study vaccine. Exclusion Criteria: History of active hepatitis within the prior 3 months History of diabetic ketoacidosis, or >1 episodes of severe, symptomatic hypoglycemia within the prior 3 months Myocardial infarction, acute coronary syndrome, transient ischemic attack, and ischemic or hemorrhagic stroke within the prior 3 months History of severe pulmonary hypertension or history of Eisenmenger syndrome History of invasive pneumococcal disease (IPD) or known history of other culture-positive pneumococcal disease within the prior 3 years Known hypersensitivity to any vaccine component, pneumococcal conjugate vaccine, or diphtheria toxoid-containing vaccine Known or suspected impairment of immunological function (including human immunodeficiency virus (HIV) infection or autoimmune disease) History of malignancy within the prior 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer History of Stage 4 or 5 Chronic Kidney Disease or nephrotic syndrome History of alcohol withdrawal or alcohol withdrawal seizure within the prior 12 months History of coagulation disorder contraindicating intramuscular vaccination History of hospitalization within the prior 3 months Planned organ transplantation (heart, liver, lung, kidney, or pancreas) or other planned major surgery during the duration of this study. Expected survival for less than 1 year according to the investigator's judgment. Female participant: positive urine or serum pregnancy test Prior administration of any pneumococcal vaccine Received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for ≥14 consecutive days and has not completed within the prior 30 days Received systemic corticosteroids exceeding physiologic replacement doses within 14 days before study vaccination Receiving immunosuppressive or immunomodulatory therapy with a biological agent Received any licensed, non-live vaccine within 14 days before receipt of study vaccine or is scheduled to receive any licensed, non-live vaccine within 30 days following receipt of study vaccine Received any live vaccine within 30 days before receipt of any study vaccine or is scheduled to receive any live vaccine within 30 days following receipt of any study vaccine Received a blood transfusion or blood products within the prior 6 months Receiving chronic home oxygen therapy Participated in another clinical study of an investigational product within the prior 2 months Current user of recreational or illicit drugs or history of drug abuse or dependence Diabetes mellitus with HgA1c ≥10% Chronic liver disease with Child-Pugh Class B or C cirrhosis Chronic lung disease with Chronic Obstructive Pulmonary Disease (COPD) GOLD Stage 4 or severe persistent asthma Chronic heart disease with NYHA heart failure Class 4.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: V114<br>Participants will receive a single 0.5 mL intramuscular (IM) injection of V114 on Day 1 (Vaccination 1) and a single 0.5 mL IM injection of PNEUMOVAX™23 at Month 6 (Vaccination 2) | Biological: V114<br>* 15-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 33F (2 mcg each), serotype 6B (4 mcg) and Merck Aluminum Phosphate Adjuvant (125 mcg) in each 0.5 mL dose<br>Biological: PNEUMOVAX™23<br>* 23-valent pneumococcal polysaccharide vaccine with serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F (25 mcg each) in each 0.5 mL dose<br>* Other names: PPV23;|
| Active Comparator: Prevnar 13™<br>Participants will receive a single 0.5 mL IM injection of Prevnar 13™ on Day 1 (Vaccination 1) and a single 0.5 mL IM injection of PNEUMOVAX™23 at Month 6 (Vaccination 2) | Biological: Prevnar 13™<br>* 13-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F (2.2 mcg) and 6B (4.4 mcg), and aluminum phosphate adjuvant (125 mcg aluminum) in each 0.5 ml dose<br>* Other names: PCV13;Biological: PNEUMOVAX™23<br>* 23-valent pneumococcal polysaccharide vaccine with serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F (25 mcg each) in each 0.5 mL dose<br>* Other names: PPV23;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Solicited Injection-site Adverse Events Following V114 or Prevnar 13™ | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Following Vaccination 1 with either V114 or Prevnar 13™, the percentage of participants with solicited injection-site AEs was assessed. The solicited injection-site AEs assessed were redness/erythema, swelling, and tenderness/pain. Estimated confidence intervals (CIs) are calculated based on the exact binomial method proposed by Clopper and Pearson. | Up to 5 days after Vaccination 1 | 
| Percentage of Participants With Solicited Systemic Adverse Events Following V114 or Prevnar 13™ | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Following vaccination with V114 or Prevnar 13™, the percentage of participants with solicited systemic AEs was assessed. The solicited systemic AEs assessed were muscle pain/myalgia, joint pain/arthralgia, headache, and tiredness/fatigue. Estimated CIs are calculated based on the exact binomial method proposed by Clopper and Pearson. | Up to 14 days after Vaccination 1 | 
| Percentage of Participants With a Vaccine-related Serious Adverse Event Following V114 or Prevnar 13™ | A serious adverse event (SAE) is an AE that is life-threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. Relatedness of an SAE to the study vaccine was determined by the investigator. Following vaccination with V114 or Prevnar 13™, the percentage of serious adverse events of V114 compared with Prevnar 13™ was assessed. Estimated CIs are calculated based on the exact binomial method proposed by Clopper and Pearson. | Up to Month 6 (before Vaccination 2) | 
| Geometric Mean Titer of Serotype-specific Opsonophagocytic Activity Day 30 Following V114 or Prevnar 13™ | The geometric mean titer (GMT) of serotype-specific opsonophagocytic activity (OPA) for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a multiplex opsonophagocytic assay. The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Solicited Injection-site Adverse Events Following PNEUMOVAX™23 | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following Vaccination 2 with PNEUMOVAX™23, the percentage of participants with solicited injection-site AEs was assessed. The solicited injection-site AEs assessed were redness/erythema, swelling, and tenderness/pain. Estimated CIs are calculated based on the exact binomial method proposed by Clopper and Pearson and are provided in accordance with the statistical analysis plan. | Up to 5 days after Vaccination 2 (Month 6) | 
| Percentage of Participants With Solicited Systemic Adverse Events Following PNEUMOVAX™23 | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Following Vaccination 2 with PNEUMOVAX™23, the percentage of participants with solicited systemic AEs was assessed. The solicited systemic AEs assessed were muscle pain/myalgia, joint pain/arthralgia, headache, and tiredness/fatigue. Estimated CIs are calculated based on the exact binomial method proposed by Clopper and Pearson. | Up to 14 days after Vaccination 2 (Month 6) | 
| Percentage of Participants With a Vaccine-related Serious Adverse Event Following PNEUMOVAX™23 | A serious adverse event (SAE) is an AE that is life-threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. Relatedness of an SAE to the study vaccine was determined by the investigator. Following vaccination with PNEUMOVAX™23, the percentage of serious adverse events of V114 compared with Prevnar 13™ was assessed. Estimated CIs are calculated based on the exact binomial method proposed by Clopper and Pearson. | From Month 6 (before Vaccination 2) to Month 7 | 
| Geometric Mean Concentration of Serotype-specific Immunoglobulin G at Day 30 | The geometric mean concentration (GMC) of serotype-specific immunoglobulin G (IgG) for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | Day 30 | 
| Geometric Mean Fold Rise in Serotype-specific OPA Day 1 to Day 30 | Activity for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a Multiplex Opsonophagocytic Assay. Geometric mean fold rise (GMFR) is the geometric mean of fold rise from baseline to postvaccination. | Day 1 (Baseline) and Day 30 | 
| GMFR in Serotype-specific IgG Day 1 to Day 30 | IgG for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. | Day 1 (Baseline) and Day 30 | 
| Percentage of Participants With ≥4-Fold Rise in Serotype-specific OPA Day 1 to Day 30 | Activity for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a Multiplexed Opsonophagocytic Assay. The percentage of participants who had ≥4-fold rise in OPA titers were calculated from baseline to postvaccination. | Day 1 (Baseline) and Day 30 | 
| Percentage of Participants With ≥4-Fold Rise in Serotype-specific IgG Day 1 to Day 30 | IgG for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. The percentage of participants who had ≥ 4-fold rise in IgG concentration are calculated from baseline to postvaccination. | Day 1 (Baseline) and Day 30 | 
| Geometric Mean Titer of Serotype-specific OPA at Month 7 | The geometric mean titer (GMT) of serotype-specific OPA for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a multiplex opsonophagocytic assay. The within-group 95% CIs are obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. | Month 7 | 
| Geometric Mean Concentration of Serotype-specific IgG at Month 7 | The geometric mean concentration (GMC) of serotype-specific immunoglobulin G (IgG) for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. | Month 7 | 
| GMFR in Serotype-specific OPA Day 1 to Month 7 | Activity for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a Multiplexed Opsonophagocytic Assay. Geometric mean fold rise (GMFR) is the geometric mean of fold rise from baseline to postvaccination. | Day 1 (Baseline) and Month 7 | 
| GMFR in Serotype-specific IgG Day 1 to Month 7 | IgG for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. | Day 1 (Baseline) and Month 7 | 
| Percentage of Participants With ≥4-Fold Rise in Serotype-specific OPA Day 1 to Month 7 | Activity for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a Multiplexed Opsonophagocytic Assay. The percentage of participants who had ≥4-fold rise in OPA titers were calculated from baseline to postvaccination. | Day 1 (Baseline) and Month 7 | 
| Percentage of Participants With ≥4-Fold Rise in Serotype-specific IgG Day 1 to Month 7 | IgG for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. The percentage of participants who had ≥ 4-fold rise in IgG concentration are calculated from baseline to postvaccination. | Day 1 (Baseline) and Month 7 | 
| GMFR in Serotype-specific OPA Month 6 to Month 7 | Activity for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using the Multiplexed Opsonophagocytic Assay. Geometric mean fold rise (GMFR) is the geometric mean of fold rise from baseline to postvaccination. | Month 6 (Baseline before Vaccination 2) and Month 7 | 
| GMFR in Serotype-specific IgG Month 6 to Month 7 | IgG for the serotypes contained in Prevnar 13™ and V114 and (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. GMFR is the geometric mean of fold rise from baseline to postvaccination. | Month 6 (Baseline before Vaccination 2) and Month 7 | 
| Percentage of Participants With ≥4-Fold Rise in Serotype-specific OPA Month 6 to Month 7 | Activity for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a Multiplexed Opsonophagocytic Assay. The percentage of participants who had ≥4-fold rise in OPA titers were calculated from baseline to postvaccination. | Month 6 (Baseline before Vaccination 2) and Month 7 | 
| Percentage of Participants With ≥4-Fold Rise in Serotype-specific IgG Month 6 to Month 7 | IgG for the serotypes contained in Prevnar 13™ and V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. The percentage of participants who had ≥ 4-fold rise in IgG concentration are calculated from baseline to postvaccination. | Month 6 (Baseline before Vaccination 2) and Month 7 |