Rheumatoid Arthritis
Conditions
Brief summary
This study will evaluate immune response following administration of zoster vaccine in subjects with rheumatoid arthritis who are receiving background methotrexate and initiate 5 mg twice daily of tofacitinib or placebo for tofacitinib 2 to 3 weeks following vaccination.
Interventions
DRUGTofacitinib
5 mg twice daily of tofacitinib with background methotrexate for 12 weeks
DRUGPlacebo
Placebo tablets twice daily with background methotrexate for 12 weeks
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have moderate to severe rheumatoid arthritis inadequately controlled by methotrexate as defined by the American College of Rheumatology (ACR) classification criteria for Rheumatoid arthritis, painful and swollen joint counts and C-reactive protein (CRP). * Screening CRP \>3 mg/L or CDAI score \> 10 at screening or at baseline before vaccination. * Subjects must have active disease at screening and baseline. * Must be at least 50 years of age or older.
Exclusion criteria
* History of receiving any varicella-zoster virus vaccine * Receipt of any vaccines within 6 weeks of first dose of study treatment. * Subjects with current infections or history of infections. * History of recurrent (more than one episode) of herpes zoster or disseminated (a single episode) of herpes zoster or disseminated (a single episode) of herpes simplex.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fold Change From Baseline in Varicella Zoster Virus (VZV)-Specific Immunoglobulin G (IgG) Levels at Week 4 | Baseline (pre-vaccination; Day -14), Week 4 (6 weeks post-vaccination) | VZV-specific IgG levels as measured by enzyme-linked immunosorbent assay (ELISA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fold Change From Baseline in VZV-Specific IgG Levels at Day 1 and Week 12 | Baseline (pre-vaccination; Day -14), Day 1 (2 weeks post-vaccination), Week 12 (14 weeks post-vaccination) | — |
| Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12 | Day 1 (2 weeks post-vaccination), Week 4 (6 weeks post-vaccination), Week 12 (14 weeks post-vaccination) | The absolute geometric mean titer (GMT) of VZV-specific IgG levels was calculated from logarithmically transformed assay values. |
| Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12 | Day 1 (2 weeks post-vaccination), Week 4 (6 weeks post-vaccination), Week 12 (14 weeks post-vaccination) | VZV-specific IgG levels as measured by ELISA. A ratio greater than or equal to (\>=)1.5 was defined as a responder. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Baseline up to Week 16 | An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE 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. Treatment-emergent are events between first dose of study drug and up to Week 16 that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs. |
| Number of Participants With Zoster Vaccine-Related AEs by System Organ Class | Baseline up to Week 16 | Zoster vaccine-related AEs included General Disorders and Administration Site Conditions (injection site erythema, pain, pruritis, rash, swelling; vaccination site erythema, pruritus, rash), Infections and Infestations (disseminated herpes zoster), and Musculoskeletal and Connective Tissue Disorders (myalgia). All zoster vaccine-related AEs were mild, except for the herpes zoster AE classified under Infections and Infestations, which was moderate in severity. |
| Number of Participants With Clinical Herpes Zoster Events by Severity | Baseline up to Week 16 | Clinical herpes is manifested as mild, moderate, or severe disseminated herpes zoster. |
| Number of Participants With Clinically Significant Abnormal Laboratory Parameters | Baseline up to Week 16 | Participants with the following abnormalities were discontinued from the study: 2 sequential absolute neutrophil counts (ANC) \<1000/mm\^3; 2 sequential hemoglobin values \<8.0 g/dL or decreases of \>30% from baseline value; 2 sequential absolute lymphocyte count \<500/mm\^3; 2 sequential platelet counts \<75,000/mm\^3; 2 sequential alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations \>=3 times the upper limit of normal (X ULN) with a total bilirubin value \>=2X ULN, elevated international normalized ratio (INR), or accompanied by signs/symptoms consistent with hepatic injury; 2 sequential ALT or AST elevations \>=5X ULN regardless of total bilirubin or accompanying symptoms; confirmed increases in serum creatinine (SCr) \>50% over the average of screening and baseline values; a confirmed positive urine pregnancy test or refusal to use appropriate contraception in a woman of childbearing potential. |
Countries
United States
Participant flow
Pre-assignment details
The zoster vaccine was administered at least 2 weeks (14 to 21 days) prior to initiation of CP-690,550 (tofacitinib) or placebo in rheumatoid arthritis (RA) participants on background methotrexate therapy.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Twice a Day Following administration of zoster vaccine, participants with Rheumatoid Arthritis (RA) on background methotrexate received placebo matched tofacitinib tablets twice a day orally for up to 12 weeks. | 57 |
| Tofacitinib 5 mg Twice a Day Following administration of zoster vaccine to RA participants receiving background methotrexate, participants received tofacitinib 5 mg twice a day orally for up to 12 weeks. | 55 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 4 |
| Overall Study | Lack of Efficacy | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo Twice a Day | Tofacitinib 5 mg Twice a Day | Total |
|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 8.7 | 61.7 years STANDARD_DEVIATION 6.2 | 61.8 years STANDARD_DEVIATION 7.6 |
| Sex: Female, Male Female | 38 Participants | 42 Participants | 80 Participants |
| Sex: Female, Male Male | 19 Participants | 13 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 57 | 6 / 55 |
| serious Total, serious adverse events | 0 / 57 | 3 / 55 |
Outcome results
Primary
Fold Change From Baseline in Varicella Zoster Virus (VZV)-Specific Immunoglobulin G (IgG) Levels at Week 4
VZV-specific IgG levels as measured by enzyme-linked immunosorbent assay (ELISA).
Time frame: Baseline (pre-vaccination; Day -14), Week 4 (6 weeks post-vaccination)
Population: The evaluable immunogenicity analysis population included randomized participants who had at least 1 dose of study drug (tofacitinib or placebo) and who complied closely with protocol eligibility criteria, visit windows for study procedures, had valid assay results at the primary visits and no major protocol deviations.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo Twice a Day | Fold Change From Baseline in Varicella Zoster Virus (VZV)-Specific Immunoglobulin G (IgG) Levels at Week 4 | 1.736 fold rise |
| Tofacitinib 5 mg Twice a Day | Fold Change From Baseline in Varicella Zoster Virus (VZV)-Specific Immunoglobulin G (IgG) Levels at Week 4 | 2.105 fold rise |
Comparison: Geometric Mean Fold Rise (GMFR) for Tofacitinib versus Placebo (Week 4)80% CI: [1.033, 1.424]ANCOVA
Secondary
Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12
The absolute geometric mean titer (GMT) of VZV-specific IgG levels was calculated from logarithmically transformed assay values.
Time frame: Day 1 (2 weeks post-vaccination), Week 4 (6 weeks post-vaccination), Week 12 (14 weeks post-vaccination)
Population: The evaluable immunogenicity analysis population included randomized participants who had at least 1 dose of study drug (tofacitinib or placebo) and who complied closely with protocol eligibility criteria, visit windows for study procedures, had valid assay results at the primary visits and no major protocol deviations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Placebo Twice a Day | Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12 | Day 1 | 361.603 [gp]ELISA units/mL |
| Placebo Twice a Day | Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12 | Week 4 | 322.486 [gp]ELISA units/mL |
| Placebo Twice a Day | Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12 | Week 12 | 278.599 [gp]ELISA units/mL |
| Tofacitinib 5 mg Twice a Day | Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12 | Day 1 | 384.219 [gp]ELISA units/mL |
| Tofacitinib 5 mg Twice a Day | Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12 | Week 4 | 403.422 [gp]ELISA units/mL |
| Tofacitinib 5 mg Twice a Day | Absolute Values in VZV-Specific IgG Levels at Day 1, Week 4 and Week 12 | Week 12 | 312.328 [gp]ELISA units/mL |
Comparison: Geometric Mean Titer (GMT) for Tofacitinib versus Placebo (Day 1)80% CI: [0.821, 1.375]ANCOVA
Comparison: GMT for Tofacitinib versus Placebo (Week 4)80% CI: [0.967, 1.618]ANCOVA
Comparison: GMT for Tofacitinib versus Placebo (Week 12)80% CI: [0.862, 1.459]ANCOVA
Secondary
Fold Change From Baseline in VZV-Specific IgG Levels at Day 1 and Week 12
Time frame: Baseline (pre-vaccination; Day -14), Day 1 (2 weeks post-vaccination), Week 12 (14 weeks post-vaccination)
Population: The evaluable immunogenicity analysis population included randomized participants who had at least 1 dose of study drug (tofacitinib or placebo) and who complied closely with protocol eligibility criteria, visit windows for study procedures, had valid assay results at the primary visits and no major protocol deviations.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Placebo Twice a Day | Fold Change From Baseline in VZV-Specific IgG Levels at Day 1 and Week 12 | Day 1 | 1.947 fold rise |
| Placebo Twice a Day | Fold Change From Baseline in VZV-Specific IgG Levels at Day 1 and Week 12 | Week 12 | 1.496 fold rise |
| Tofacitinib 5 mg Twice a Day | Fold Change From Baseline in VZV-Specific IgG Levels at Day 1 and Week 12 | Day 1 | 2.005 fold rise |
| Tofacitinib 5 mg Twice a Day | Fold Change From Baseline in VZV-Specific IgG Levels at Day 1 and Week 12 | Week 12 | 1.636 fold rise |
Comparison: GMFR for Tofacitinib versus Placebo (Day 1)80% CI: [0.877, 1.209]ANCOVA
Comparison: GMFR for Tofacitinib versus Placebo (Week 12)80% CI: [0.924, 1.294]ANCOVA
Secondary
Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12
VZV-specific IgG levels as measured by ELISA. A ratio greater than or equal to (\>=)1.5 was defined as a responder.
Time frame: Day 1 (2 weeks post-vaccination), Week 4 (6 weeks post-vaccination), Week 12 (14 weeks post-vaccination)
Population: The evaluable immunogenicity analysis population included randomized participants who had at least 1 dose of study drug (tofacitinib or placebo) and who complied closely with protocol eligibility criteria, visit windows for study procedures, had valid assay results at the primary visits and no major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Twice a Day | Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12 | Day 1 | 47.17 percentage of participants |
| Placebo Twice a Day | Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12 | Week 4 | 43.40 percentage of participants |
| Placebo Twice a Day | Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12 | Week 12 | 43.18 percentage of participants |
| Tofacitinib 5 mg Twice a Day | Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12 | Day 1 | 55.56 percentage of participants |
| Tofacitinib 5 mg Twice a Day | Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12 | Week 4 | 57.41 percentage of participants |
| Tofacitinib 5 mg Twice a Day | Percentage of Participants With >=1.5 Fold Change in VZV-Specific IgG Levels Day 1, Week 4 and Week 12 | Week 12 | 45.83 percentage of participants |
Comparison: Tofacitinib versus Placebo (Day 1)80% CI: [-4.05, 20.56]80% CI based on Chan and Zhang method
Comparison: Tofacitinib versus Placebo (Week 4)80% CI: [1.57, 26.03]80% CI based on Chan and Zhang method
Comparison: Tofacitinib versus Placebo (Week 12)80% CI: [-10.66, 15.83]80% CI based on Chan and Zhang method
Other Pre-specified
Number of Participants With Clinical Herpes Zoster Events by Severity
Clinical herpes is manifested as mild, moderate, or severe disseminated herpes zoster.
Time frame: Baseline up to Week 16
Population: The safety analysis population included randomized participants who received at least 1 dose of the study drug (tofacitinib or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Twice a Day | Number of Participants With Clinical Herpes Zoster Events by Severity | Mild Herpes Zoster | 0 participants |
| Placebo Twice a Day | Number of Participants With Clinical Herpes Zoster Events by Severity | Moderate Herpes Zoster | 0 participants |
| Placebo Twice a Day | Number of Participants With Clinical Herpes Zoster Events by Severity | Severe Herpes Zoster | 0 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Clinical Herpes Zoster Events by Severity | Mild Herpes Zoster | 0 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Clinical Herpes Zoster Events by Severity | Moderate Herpes Zoster | 1 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Clinical Herpes Zoster Events by Severity | Severe Herpes Zoster | 0 participants |
Other Pre-specified
Number of Participants With Clinically Significant Abnormal Laboratory Parameters
Participants with the following abnormalities were discontinued from the study: 2 sequential absolute neutrophil counts (ANC) \<1000/mm\^3; 2 sequential hemoglobin values \<8.0 g/dL or decreases of \>30% from baseline value; 2 sequential absolute lymphocyte count \<500/mm\^3; 2 sequential platelet counts \<75,000/mm\^3; 2 sequential alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations \>=3 times the upper limit of normal (X ULN) with a total bilirubin value \>=2X ULN, elevated international normalized ratio (INR), or accompanied by signs/symptoms consistent with hepatic injury; 2 sequential ALT or AST elevations \>=5X ULN regardless of total bilirubin or accompanying symptoms; confirmed increases in serum creatinine (SCr) \>50% over the average of screening and baseline values; a confirmed positive urine pregnancy test or refusal to use appropriate contraception in a woman of childbearing potential.
Time frame: Baseline up to Week 16
Population: The safety analysis population included randomized participants who received at least 1 dose of the study drug (tofacitinib or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Twice a Day | Number of Participants With Clinically Significant Abnormal Laboratory Parameters | 1 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Clinically Significant Abnormal Laboratory Parameters | 0 participants |
Other Pre-specified
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a participant who received study drug. An SAE was an AE 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. Treatment-emergent are events between first dose of study drug and up to Week 16 that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.
Time frame: Baseline up to Week 16
Population: The safety analysis population included randomized participants who received at least 1 dose of the study drug (tofacitinib or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 21 participants |
| Placebo Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | AEs | 16 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | SAEs | 3 participants |
Other Pre-specified
Number of Participants With Zoster Vaccine-Related AEs by System Organ Class
Zoster vaccine-related AEs included General Disorders and Administration Site Conditions (injection site erythema, pain, pruritis, rash, swelling; vaccination site erythema, pruritus, rash), Infections and Infestations (disseminated herpes zoster), and Musculoskeletal and Connective Tissue Disorders (myalgia). All zoster vaccine-related AEs were mild, except for the herpes zoster AE classified under Infections and Infestations, which was moderate in severity.
Time frame: Baseline up to Week 16
Population: The safety analysis population included randomized participants who received at least 1 dose of the study drug (tofacitinib or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Twice a Day | Number of Participants With Zoster Vaccine-Related AEs by System Organ Class | General and Administration Site Conditions | 2 participants |
| Placebo Twice a Day | Number of Participants With Zoster Vaccine-Related AEs by System Organ Class | Infections and Infestations | 0 participants |
| Placebo Twice a Day | Number of Participants With Zoster Vaccine-Related AEs by System Organ Class | Musculoskeletal and Connective Tissue Disorders | 0 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Zoster Vaccine-Related AEs by System Organ Class | General and Administration Site Conditions | 4 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Zoster Vaccine-Related AEs by System Organ Class | Infections and Infestations | 1 participants |
| Tofacitinib 5 mg Twice a Day | Number of Participants With Zoster Vaccine-Related AEs by System Organ Class | Musculoskeletal and Connective Tissue Disorders | 1 participants |