Influenza, Pneumococcal Pneumonia
Conditions
Keywords
quadrivalent influenza vaccine, 23-valent pneumococcal vaccine, immunogenicity
Brief summary
The immunogenicity of simultaneous administration of quadrivalent influenza vaccine and pneumococcal vaccine was unknown. The purpose of present study is to compare the immunogenicity of simultaneous administration of influenza vaccine and pneumococcal vaccine with that of separate administration.
Detailed description
The immunogenicity of simultaneous administration of quadrivalent influenza vaccine and pneumococcal vaccine was unknown. We compare the immunogenicity of simultaneous administration of quadrivalent influenza vaccine and pneumococcal vaccine with that of separate administration. 162 Participants are randomly assigned to one of the two study groups; Simultaneous administration group: receive injections of pneumococcal vaccine and influenza vaccine simultaneously. Sequential administration group: receive injections of pneumococcal vaccine 2 weeks after the injection of the influenza vaccine. We compare the immunogenicity of the two groups.
Interventions
BIOLOGICALSimultaneous administration of Pneumovax NP® and Fluvic HA syringe®
Injections of pneumococcal vaccine and influenza vaccine simultaneously.
BIOLOGICALSequential administration of Pneumovax NP® and Fluvic HA syringe®
Injections of pneumococcal vaccine 2 weeks after the injection of the influenza vaccine.
Sponsors
PPD Development, LP
Osaka University
Merck Sharp & Dohme LLC
Kameda Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adults aged ≧65 years who had never received pneumococcal vaccine and quadrivalent influenza vaccine of 2015/2016 season
Exclusion criteria
* a sensitivity to pneumococcal and influenza vaccine * received other inactivated vaccine within 14 days * received other live vaccine within 28 days * the presence of conditions known to impair pneumococcal vaccine response * having malignant disease * taking oral corticosteroids or immunosuppressive agent * history of splenectomy * history of an acute febrile illness or signs of severe acute illness at the time of vaccination * other inappropriate condition to receive vaccination * suffering an acute illness requiring antibiotics or steroids within the past month * not expected to survive 12 months were also excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients With Positive Antibody Response in Serotype 23F of Pneumococcal Antibody. | 1month after the dose of PPV23 | The primary endpoint was the number of patients with positive antibody responses (≥2-fold increase in IgG concentrations 4-6 weeks after PPSV23 vaccination) in serotype 23F of the pneumococcal antibody. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4 to 6 weeks after vaccination (P1), 24 weeks to 27 weeks after vaccination (P2) | Positive antibody response was defined as ≥2-fold increase in IgG concentrations 4-6 weeks after PPSV23 vaccination in respective serotypes of the pneumococcal antibody. |
| The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination (at baseline; in designated P0), 4 to 6 weeks after vaccination (P1), 24 weeks to 27 weeks after vaccination (P2) | Pneumococcal IgG concentrations were converted using natural log transformations and presented as a geometric mean concentration. |
| The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination (I1) and 24 weeks to 27 weeks after vaccination (I2) | Seroprotection rates (post-vaccination titer ≥1:40) were calculated to assess the immunogenicity of influenza vaccination. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simultaneous Administration Group The subjects receive injections of pneumococcal vaccine and influenza vaccine simultaneously. We use commercially available PPV23 (Pneumovax NP®, MSDKK, Tokyo, Japan) containing 25 μg each of 23 capsular polysaccharide types. We use Fluvic HA syringe® (Handai Biken Ltd, Osaka, Japan), quadrivalent influenza vaccine (0.5ml) of 2015/2016 season.
Simultaneous administration of Pneumovax NP® and Fluvic HA syringe®: Injections of pneumococcal vaccine and influenza vaccine simultaneously. | 81 |
| Sequential Administration Group The subjects receive injections of pneumococcal vaccine 2 weeks after the injection of the influenza vaccine. We use commercially available PPV23 (Pneumovax NP®, MSDKK, Tokyo, Japan) containing 25 μg each of 23 capsular polysaccharide types. We use Fluvic HA syringe® (Handai Biken Ltd, Osaka, Japan), quadrivalent influenza vaccine (0.5ml) of 2015/2016.
Sequential administration of Pneumovax NP® and Fluvic HA syringe®: Injections of pneumococcal vaccine 2 weeks after the injection of the influenza vaccine. | 80 |
| Total | 161 |
Baseline characteristics
| Characteristic | Simultaneous Administration Group | Sequential Administration Group | Total |
|---|---|---|---|
| Age, Continuous | 71.0 years STANDARD_DEVIATION 5.1 | 70.2 years STANDARD_DEVIATION 4.1 | 70.6 years STANDARD_DEVIATION 4.6 |
| Sex: Female, Male Female | 33 Participants | 31 Participants | 64 Participants |
| Sex: Female, Male Male | 48 Participants | 49 Participants | 97 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 81 | 31 / 79 |
| serious Total, serious adverse events | 0 / 81 | 0 / 80 |
Outcome results
Primary
The Number of Patients With Positive Antibody Response in Serotype 23F of Pneumococcal Antibody.
The primary endpoint was the number of patients with positive antibody responses (≥2-fold increase in IgG concentrations 4-6 weeks after PPSV23 vaccination) in serotype 23F of the pneumococcal antibody.
Time frame: 1month after the dose of PPV23
Population: In the sequential group, 5 patients were excluded from primary analysis because of the reasons below.~1 patient: eligibility error, 1 patient: lost to follow-up (patient's decision), 3 patient: discontinued intervention (1 patient: fever, 2 patients: patient's decision
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 23F of Pneumococcal Antibody. | 63 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 23F of Pneumococcal Antibody. | 59 Participants |
Secondary
The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A)
Pneumococcal IgG concentrations were converted using natural log transformations and presented as a geometric mean concentration.
Time frame: Before vaccination (at baseline; in designated P0), 4 to 6 weeks after vaccination (P1), 24 weeks to 27 weeks after vaccination (P2)
Population: Immunogenicity was assessed in patients who received the allocated intervention (i.e., received at least 1 dose of the study vaccine), and had a blood sample taken within the planned time period.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 23F | 0.40 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 3 | 0.07 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 4 | 0.08 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 6B | 0.24 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 14 | 0.68 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 19A | 0.72 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 23F | 2.04 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 3 | 0.24 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 4 | 0.24 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 6B | 0.96 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 14 | 2.78 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 19A | 3.74 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 23F | 2.12 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 3 | 0.26 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 4 | 0.30 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 6B | 1.18 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 14 | 3.57 micrograms per milliliter |
| Simultaneous Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 19A | 4.61 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 3 | 0.24 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 23F | 0.20 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 6B | 0.96 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 3 | 0.07 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 19A | 3.38 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 4 | 0.05 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 14 | 4.72 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 6B | 0.14 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 4 | 0.36 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 14 | 0.42 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 19A | 2.92 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | Before vaccination 19A | 0.49 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 14 | 6.21 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 23F | 1.41 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 23F | 1.70 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 3 | 0.21 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 24-27 weeks after vaccination 6B | 1.29 micrograms per milliliter |
| Sequential Administration Group | The Geometric Mean Concentrations of Specific Antibodies to the 6 Serotypes (23F, 3, 4, 6B 14 and 19A) | 4-6 weeks after vaccination 4 | 0.28 micrograms per milliliter |
Secondary
The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody.
Positive antibody response was defined as ≥2-fold increase in IgG concentrations 4-6 weeks after PPSV23 vaccination in respective serotypes of the pneumococcal antibody.
Time frame: 4 to 6 weeks after vaccination (P1), 24 weeks to 27 weeks after vaccination (P2)
Population: Immunogenicity was assessed in patients who received the allocated intervention (i.e., received at least 1 dose of the study vaccine), and had a blood sample taken within the planned time period.intervention (1 patient: fever, 2 patients: patient's decision
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 3 | 56 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 4 | 54 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 6B | 59 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 14 | 49 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 19A | 61 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 3 | 59 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 4 | 58 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 6B | 66 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 14 | 59 Participants |
| Simultaneous Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 19A | 67 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 6B | 63 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 3 | 52 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 3 | 51 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 4 | 66 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 19A | 63 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 6B | 63 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 4 | 67 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 14 | 67 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 24-27 weeks after vaccination 14 | 66 Participants |
| Sequential Administration Group | The Number of Patients With Positive Antibody Response in Serotype 3, 4, 6B, 1 4 and 19A of Pneumococcal Antibody. | 4-6 weeks after vaccination 19A | 59 Participants |
Secondary
The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine.
Seroprotection rates (post-vaccination titer ≥1:40) were calculated to assess the immunogenicity of influenza vaccination.
Time frame: 4 to 6 weeks after vaccination (I1) and 24 weeks to 27 weeks after vaccination (I2)
Population: Immunogenicity was assessed in patients who received the allocated intervention (i.e., received at least 1 dose of the study vaccine), and had a blood sample taken within the planned time period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : H1N1 | 68 Participants |
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : H3N2 | 66 Participants |
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : B texas | 33 Participants |
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : B Phuket | 49 Participants |
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : H1N1 | 41 Participants |
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : H3N2 | 47 Participants |
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : B texas | 18 Participants |
| Simultaneous Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : B Phuket | 24 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : B Phuket | 16 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : H1N1 | 60 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : H1N1 | 46 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : H3N2 | 68 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : B texas | 11 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : B texas | 45 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 24 weeks to 27 weeks after vaccination : H3N2 | 44 Participants |
| Sequential Administration Group | The Number of Patients With Seroprotection Rate in Quadrivalent Influenza Vaccine. | 4 to 6 weeks after vaccination : B Phuket | 48 Participants |