A Study to Assess the Safety, Tolerability, and Immunogenicity of RSVpreF in Adults at High Risk of Severe RSV Disease

Study Overview
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Brief Summary
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The purpose of this study is to learn about the safety and immunogenicity of a study vaccine (called RSVpreF) in several adult groups. Respiratory Syncytial Virus (RSV) is a common type of virus (germ) that can cause severe illness, where medical help is needed. RSV can lead to airway diseases in all ages. Vaccines help your body make antibodies which help fight against diseases. This is called an immune response. This study will measure how much antibody participants make after receiving RSVpreF (immunogenicity). The study consists of 2 groups (Substudy A and Substudy B). Substudy A is seeking approximately 675 participants who are: Between 18 and 60 years of age. Considered having a high likelihood of severe RSV disease due to certain long-term medical conditions. Such medical conditions do not include immunocompromising conditions. Participants will need to come to the study clinic at least 2 times. At the first clinic visit, participants will receive 1 shot of RSVpreF or placebo in the arm by chance. A placebo looks like the study vaccine but contains no active ingredients. At each clinic visit, a blood sample will be taken. A third (final) visit can be either completed in clinic or via telephone contact. This study is about 6 months long for each participant. Substudy B is seeking approximately 200 participants who are: At least 18 years of age. About half of the participants will be at least 60 years of age. Considered having a weakened immune system (immunocompromised). Participants will need to come to the study clinic at least 3 times. All participants will receive a shot of RSVpreF at the first study clinic visit. The second study clinic visit will be 1 month later. All participants will receive a second shot of the study vaccine at this second study clinic visit. Blood samples will be taken at the 3 study clinic visits. A fourth (final) visit can be either completed in clinic or via telephone contact. This study is about 7 months long for each participant.

Detailed Description
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This is a Phase 3 protocol that will assess the safety, tolerability, and immunogenicity of Pfizer's RSVpreF in adults at high risk of severe RSV disease. Each substudy design is detailed separately, and these substudies may be conducted in parallel, as required by the clinical plan, within the framework of this protocol. Substudy A Design: This is a Phase 3, multicenter, randomized, double-blinded, placebo-controlled study that will assess the safety, tolerability, and immunogenicity of Pfizer's RSVpreF in adults 18 to <60 years of age considered to be at high risk of RSV disease due to certain chronic medical conditions. Approximately 675 participants ≥18 to <60 years of age considered at high risk of RSV disease due to certain chronic medical conditions, excluding immunocompromising conditions, will be randomized to receive a single 120-µg dose of RSVpreF or placebo in a 2:1 ratio. Enrollment will be monitored to help ensure distribution of vaccination across the age range. The duration of study participation for each participant will be 6 months, with 3 scheduled visits. All participants will have blood drawn at baseline prior to vaccination and at 1 month after vaccination to assess immunogenicity. Immunogenicity elicited at 1 month after vaccination with RSVpreF in Substudy A will be bridged to the immunogenicity of participants 60 years of age and older in the C3671013 study, in which RSVpreF efficacy was demonstrated. Local reaction and systemic event data will be collected in an e-diary for 7 days after study vaccination (Days 1 through 7, where Day 1 is the day of vaccination). Reported Grade 3 reactogenicity will be assessed by the study site to determine if an unscheduled visit is required. For all participants, AEs will be collected from informed consent through 1 month following study intervention administration, and AESIs, NDCMCs and SAEs will be collected from informed consent throughout study participation. In addition, AEs occurring up to 48 hours after blood draws that are related to study procedures will be collected. Substudy B Design: This is a Phase 3, single-arm, open-label, multicenter study that will assess the safety, tolerability, and immunogenicity of Pfizer's RSVpreF in immunocompromised adults. Substudy B included approximately 200 immunocompromised adults ≥18 years of age, that will receive 2 120-µg doses of RSVpreF with an interval of 1 month. Approximately 100 participants will be ≥60 years of age and approximately 100 participants will be ≥18 to 60 years of age. Enrollment will be monitored to help ensure distribution of vaccination across the age ranges and underlying immunocompromising conditions. The duration of study participation for each participant will be 7 months, with 4 scheduled visits. All participants will have blood drawn at baseline prior to vaccination and at 1 month after (each) vaccination to assess immunogenicity. Local reaction and systemic event data will be collected in an e-diary for 7 days after study vaccination (Days 1 through 7, where Day 1 is the day of vaccination). Reported Grade 3 reactogenicity will be assessed by the study site to determine if an unscheduled visit is required. For all participants, AEs will be collected from informed consent through 1 month following the last study intervention administration, and AESIs, NDCMCs and SAEs will be collected from informed consent throughout study participation. In addition, AEs occurring up to 48 hours after blood draws that are related to study procedures will be collected.

Official Title
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A PHASE 3 PROTOCOL TO EVALUATE THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF RESPIRATORY SYNCYTIAL VIRUS (RSV) PREFUSION F SUBUNIT VACCINE IN ADULTS AT HIGH RISK OF SEVERE RSV DISEASE

Conditions
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RESPIRATORY SYNCYTIAL VIRUS (RSV)

Intervention / Treatment
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* Biological: RSVpreF
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Substudy A Inclusion Criteria: Capable of giving signed informed consent as described per protocol. Participants ≥18 to <60 years of age at study enrollment. Life expectancy ≥12 months (365 days) in the opinion of the investigator at enrollment. Participants who are willing and able to comply with all scheduled visits, vaccination plan, lifestyle considerations, and other study procedures. Participants who are considered at high risk of RSV disease by virtue of the following: Adults with chronic pulmonary (including asthma), cardiovascular (excluding isolated hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus). Chronic medical conditions for this substudy are defined as: - Duration greater than 6 months. Stable disease not requiring a significant change in therapy in the previous 6 weeks or hospitalization for worsening disease within 12 weeks before receipt of study intervention. Requires regular medical follow-up or ongoing medication or hospitalization in the previous year. • Additional groups at high risk include: Residents of nursing homes and other long-term care facilities. Substudy A Exclusion Criteria: Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s) or any related vaccine. Participants who do not have adequate deltoid muscle mass to allow intramuscular vaccination, in the opinion of the investigator. Serious chronic disorder, including metastatic malignancy, end-stage renal disease with or without dialysis, clinically unstable cardiac disease, or any other disorder that, in the investigator's opinion, excludes the participant from participating in the study. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Note: Specific criteria for participants with known stable infection with HIV can be found in protocol. Individuals who receive chronic systemic treatment with immunosuppressive therapy, including cytotoxic agents, immunosuppressive monoclonal antibodies, systemic corticosteroids*, eg, for cancer or an autoimmune disease, or radiotherapy, from 60 days before study intervention administration or planned receipt throughout the study. *Applies to systemic corticosteroids administered for ≥14 days at a dose of ≥20 mg/day of prednisone or equivalent (eg, for cancer or an autoimmune disease). Systemic corticosteroids administered at a dose of <20 mg/day of prednisone or equivalent are permitted. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin, eyes, or ears) corticosteroids are permitted. Receipt of blood/plasma products or immunoglobulin within 60 days before study intervention administration or planned receipt of these medications prior to the final blood draw. Note: Monoclonal antibodies with targeted mechanisms of action used in the management of chronic illnesses (eg, migraine headaches, osteoporosis) are permitted, provided they do not meet exclusion criterion 7. Previous vaccination with any licensed or investigational RSV vaccine or planned receipt during study participation. Participation in other studies involving an investigational product within 28 days prior to consent and/or through and including the 6-month follow-up visit. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. Substudy B Inclusion Criteria Capable of giving signed informed consent as described per protocol. Participants ≥18 years of age at study enrollment. Life expectancy ≥12 months (365 days) in the opinion of the investigator at enrollment. Participants who are willing and able to comply with all scheduled visits, vaccination plan, lifestyle considerations, and other study procedures. Participants who are immunocompromised by virtue of the following: •Having known advanced NSCLC with at least 1 of the following: Has received initial or maintenance chemotherapy at least 2 weeks (14 days) before enrollment (or is treatment-naïve), and is not expected to receive chemotherapy within at least 2 weeks (14 days) after dose administration of initial vaccination or second vaccination; and/or Is receiving checkpoint inhibitor treatment (PD-1/PD-L1 inhibitor, CTLA-4 inhibitor) and has undergone at least 1 treatment cycle prior to enrollment; or Is receiving targeted drug therapy (EGFR, ALK, ROS1, BRAF, RET, MET, NTRK inhibitors) and has undergone at least 1 treatment cycle prior to enrollment. OR - Is currently undergoing maintenance hemodialysis treatment secondary to end-stage renal disease . OR - Is on active immunomodulator therapy (eg, TNFα inhibitor, tofacitinib, or MTX) for an autoimmune inflammatory disorder (eg, inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis, or inflammatory bowel disease, such as ulcerative colitis or Crohn's disease) at a stable*dose. *Stable dose is defined as receiving the same dose for at least 3 months (84 days) with no changes in the 28 days prior to enrollment. See protocol for details on stable dose for MTX. OR - Is receiving an SOT (kidney, liver, lung, or heart) at least 3 months (84 days) prior to enrollment (Visit 201) and with no acute rejection episodes within 2 months (60 days) prior to enrollment (Visit 201). Substudy B Exclusion Criteria: 1.Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection. 2.History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s) or any related vaccine. 3.Participants with a history of transplant rejection, or PTLD, or participants who have had treatment for these conditions within 3 months (84 days) prior to study enrollment. 4.Participants who do not have adequate deltoid muscle mass to allow intramuscular vaccination, in the opinion of the investigator. 5.Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Note: Specific criteria for participants with known stable infection with HIV can be found in protocol. 6.Receipt of investigational or approved monoclonal antibodies against RSV within 6 months before study intervention administration. 7.Receipt of blood/plasma products or immunoglobulin (IVIG, SCIG) within 60 days before study intervention administration or planned receipt of these medications prior to the final blood draw. Note: Please see the inclusion criteria in the protocol regarding criteria for targeted immunoglobulin therapies for underlying medical conditions. Note: Monoclonal antibodies with targeted mechanisms of action used in the management of chronic illnesses (eg, migraine headaches, osteoporosis) are permitted. 8.Previous vaccination with any licensed or investigational RSV vaccine or planned receipt during study participation. 9.Participation in other studies involving an investigational product within 28 days prior to consent and/or through and including the 6-month follow-up visit. 10.Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Interventional Model Description: Substudy A: Phase 3, multicenter, randomized, double-blinded, placebo-controlled study that will assess the safety, tolerability, and immunogenicity of Pfizer's RSVpreF in adults 18 to <60 years of age considered to be at high risk of RSV disease due to certain chronic medical conditions. Approximately 675 participants ≥18 to <60 years of age considered at high risk of RSV disease due to certain chronic medical conditions, excluding immunocompromising conditions, will be randomized to receive a single 120-µg dose of RSVpreF or placebo in a 2:1 ratio. Substudy B: Phase 3, single-arm, open-label, multicenter study that will assess the safety, tolerability, and immunogenicity of Pfizer's RSVpreF in immunocompromised adults. Approximately 200 immunocompromised adults ≥18 years of age will receive 2 120-µg doses of RSVpreF with an interval of 1 month. Approximately 100 participants will be ≥60 years of age and approximately 100 participants will be ≥18 to 60 years of age.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy A - RSVpreF<br>Participants will receive a single 120-µg dose of RSVpreF at Visit 1 | Biological: RSVpreF<br>* 120-µg<br>|
| Placebo Comparator: Substudy A - Placebo<br>Participants will receive placebo at Visit 1 | Other: Placebo<br>* Placebo<br>|
| Experimental: Substudy B - RSVpreF<br>Participants will receive 120-µg doses of RSVpreF at Visit 1 and Visit 2 (open label, single arm only) | Biological: RSVpreF<br>* 120-µg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Substudy A: Primary Safety - The proportion of participants reporting local reactions | Local reactions included pain at injection site, redness and swelling recorded by participants in an e-diary. Redness and swelling were measured and recorded in measuring device units. 1 measuring device unit =0.5 cm and graded as mild: >2.0 to 5.0 cm, moderate: > 5.0 to 10.0 cm and severe: >10 cm. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfere with daily activity and severe: prevented daily activity | Within 7 days following study administration intervention | 
| Substudy A: Primary Safety - The proportion of participants reporting systemic reactions | Systemic reactions: fever, fatigue/tiredness, headache, nausea, muscle pain, joint pain, vomiting, diarrhea and any systemic event recorded by participants in an e-diary. Fever: greater than equal to (>=) 38.0 degrees (deg) Celsius (C), mild (>=38.0 to 38.4 deg C), moderate (>38.4 to 38.9 deg C), severe (>38.9 to 40.0 deg C), and grade 4 (>40.0 deg C). Fatigue, headache, nausea, muscle pain and joint pain were graded as mild: did not interfere with activity, moderate: some interference with activity and severe: prevented daily routine activity. Vomiting was graded as mild: 1 to 2 times in 24 hours(h), moderate: >2 times in 24h and severe: requires intravenous hydration. Diarrhea was graded as mild: 2 to 3 loose stools in 24h, moderate: 4 to 5 loose stools in 24h and severe: 6 or more loose stools in 24h. | Within 7 days following study administration intervention | 
| Substudy A: Primary Safety - The proportion of participants reporting adverse events | An adverse event was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. Adverse events included both serious and non-serious adverse events. | Through 1 month following study administration intervention | 
| Substudy A: Primary Safety - The proportion of participants reporting newly diagnosed chronic medical conditions | A newly diagnosed chronic medical conditions is defined as a disease or medical condition, not previously identified, that is expected to be persistent or otherwise long-lasting in its effects (eg, asthma). | Throughout the study duration (an average of 6 months) | 
| Substudy A: Primary Safety - The proportion of participants reporting serious adverse events | Serious adverse event was an adverse event resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Throughout the study duration (an average of 6 months) | 
| Substudy A: Primary Immunogenicity - GMT ratio, estimated by the ratio of the geometric mean titers for RSV A and RSV B serum NTs with RSVpreF in Study C3671023 participants to that in Study C3671013 adults ≥60 years of age. | RSV A and RSV B neutralizing titers, expressed as geometric mean titers. geometric mean titers (GMT) ratio of the geometric mean titers for RSV A and RSV B serum neutralizing titers with RSVpreF in Study C3671023 participants to that in Study C3671013 adults ≥60 years of age. | 1 month after vaccination | 
| Substudy A: Primary Immunogenicity - Difference in seroresponse rate of RSV A and RSV B serum neutralizing titers at 1 month after vaccination with RSVpreF between participants in Study C3671023 and in Study C3671013 | Seroresponse is defined as a postvaccination neutralizing titer ≥4 times the lower limit of quantitation if baseline titer is below the lower limit of quantitation; or a ≥4-fold rise from baseline if the baseline titer is above the lower limit of quantitation | 1 month after vaccination | 
| Substudy B: Primary Safety - The proportion of participants reporting local reactions | Local reactions included pain at injection site, redness and swelling recorded by participants in an e-diary. Redness and swelling were measured and recorded in measuring device units. 1 measuring device unit =0.5 cm and graded as mild: >2.0 to 5.0 cm, moderate: > 5.0 to 10.0 cm and severe: >10 cm. Pain at injection site was graded as mild: did not interfere with daily activity, moderate: interfere with daily activity and severe: prevented daily activity | Within 7 days following study administration intervention | 
| Substudy B: Primary Safety - The proportion of participants reporting systemic reactions | Systemic reactions: fever, fatigue/tiredness, headache, nausea, muscle pain, joint pain, vomiting, diarrhea and any systemic event recorded by participants in an e-diary. Fever: greater than equal to (>=) 38.0 degrees (deg) Celsius (C), mild (>=38.0 to 38.4 deg C), moderate (>38.4 to 38.9 deg C), severe (>38.9 to 40.0 deg C), and grade 4 (>40.0 deg C). Fatigue, headache, nausea, muscle pain and joint pain were graded as mild: did not interfere with activity, moderate: some interference with activity and severe: prevented daily routine activity. Vomiting was graded as mild: 1 to 2 times in 24 hours(h), moderate: >2 times in 24h and severe: requires intravenous hydration. Diarrhea was graded as mild: 2 to 3 loose stools in 24h, moderate: 4 to 5 loose stools in 24h and severe: 6 or more loose stools in 24h. | Within 7 days following study administration intervention | 
| Substudy B: Primary Safety - The proportion of participants reporting adverse events | An adverse event was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. Adverse events included both serious and non-serious adverse events. | Through 1 month following the last dose of study intervention administration | 
| Substudy B: Primary Safety - The proportion of participants reporting newly diagnosed chronic medical donditions | A newly diagnosed chronic medical condition is defined as a disease or medical condition, not previously identified, that is expected to be persistent or otherwise long-lasting in its effects (eg, asthma). | Throughout the study duration (an average of 7 months) | 
| Substudy B: Primary Safety - The proportion of participants reporting serious adverse events | Serious adverse events was an adverse events resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Throughout the study duration (an average of 7 months) | 
| Substudy B: Primary Immunogenicity - Geometric mean titers of neutralizing titers for RSV A and RSV B | RSV A and RSV B neutralizing titers, expressed as geometric mean titers. The neutralizing titers were calculated as the interpolated reciprocal of the serum dilution resulting in 50% reduction in the number of viral focus forming units when compared to the control without test serum | At each blood sampling visit (Day 1, 1-month after vaccination 1, 1-month after vaccination 2) | 
| Substudy B: Primary Immunogenicity - Geometric mean fold rise of neutralizing titers for RSV A and RSV B | RSV A and RSV B neutralizing titers, expressed as geometric mean fold rise. The neutralizing titers were calculated as the interpolated reciprocal of the serum dilution resulting in 50% reduction in the number of viral focus forming units when compared to the control without test serum | From before vaccination to each postvaccination blood sampling visit (Day 1, 1-month after vaccination 1, 1-month after vaccination 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Substudy A: Secondary Immunogenicity - Geometric mean titers of neutralizing titers for RSV A and RSV B | RSV A and RSV B neutralizing titers, expressed as geometric mean titers. The neutralizing titers were calculated as the interpolated reciprocal of the serum dilution resulting in 50% reduction in the number of viral focus forming units when compared to the control without test serum | At each blood sampling visit (Day 1 and 1-month after vaccination) | 
| Substudy A: Secondary Immunogenicity - Geometric mean fold rise of neutralizing titers for RSV A and RSV B | RSV A and RSV B neutralizing titers, expressed as geometric mean fold rise. The neutralizing titers were calculated as the interpolated reciprocal of the serum dilution resulting in 50% reduction in the number of viral focus forming units when compared to the control without test serum | From before vaccination to the postvaccination blood sampling visit (Day 1 and 1-month after vaccination) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADULTS AT HIGH RISK, RESPIRATORY SYNCYTIAL VIRUS (RSV), IMMUNOCOMPROMISED ADULTS