Rheumatoid Arthritis
Conditions
Keywords
influenza, vaccine, pneumococcal vaccine, certolizumab pegol, Cimzia
Brief summary
The purpose of this trial is to assess the affect of Certolizumab Pegol (CZP) treatment on antibody response to T cell-independent and T cell-dependent immunizations using pneumococcal and influenza vaccines, respectively.
Interventions
OTHERPlacebo
Placebo - Two 0.9% saline subcutaneous (sc) injections at Week 0, Week 2, and Week 4 followed by two sc injections of Open-Label (OL) CZP 200 mg at Weeks 6, 8 and 10, then one sc injection of OL CZP 200 mg every two weeks from Week 12 until last drug administration (up to Week 32).
BIOLOGICALCertolizumab pegol
Certolizumab pegol - Two 200 mg subcutaneous (sc) injections at Week 0, Week 2, and Week 4 followed by one sc injection of Open-Label (OL) CZP 200 mg from Week 6 until last drug administration (up to Week 32).
Sponsors
UCB Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must be at least 18 years old at the screening visit * Subjects must be able to understand the information provided to them and to give written informed consent, and be able and willing to comply with the study requirements * Female subjects must be either postmenopausal for at least 1 year, surgically incapable of childbearing, or effectively practicing an acceptable method of contraception (either oral/parenteral/implantable hormonal contraceptives, intrauterine device or barrier and spermicide. Abstinence only is not an acceptable method. Subjects must agree to use adequate contraception during the study and for 10 weeks after the last dose of CZP. Male subjects must agree to ensure they or their female partner(s) use adequate contraception during the study and for 10 weeks after the subject receives their last dose of CZP * Subjects must have a diagnosis of adult-onset Rheumatoid Arthritis (RA) of at least 6-months duration as defined by the 1987 American College of Rheumatology (ACR) classification criteria * Subjects must have active RA disease as defined by: ≥ 4 tender joints (28 joint count) at Screening and Week 0; and ≥ 4 swollen joints (28 joint count) at Screening and Week 0
Exclusion criteria
* Subjects who have a diagnosis of any other inflammatory arthritis (eg., psoriatic arthritis or ankylosing spondylitis) * Subjects who have a history of an infected joint prosthesis at any time with that prosthesis still in situ * Subjects must be free of defined prohibited medication and biological therapy * Subjects who have received any experimental nonbiological therapy, within or outside of a clinical trial in the 3 months prior to Week 0 * Subjects who have received any experimental biological agent in the past 3 months or within 5 half-lives prior to Week 0 (whichever is longer) * Subjects who have received previous treatment with biological response modifier therapy for RA that resulted in a severe hypersensitivity reaction or an anaphylactic reaction. * Subjects with a history of pneumococcal or influenza infection in the last 3 months * Subjects with a history of pneumococcal vaccination in the last 5 years * Subjects with a history of influenza vaccination within the last 6 months * Female subjects who are breast-feeding, pregnant, or plan to become pregnant during the trial or within 3 months following last dose of study drug * Subjects with a history of chronic or recurrent infections (more than 3 episodes requiring antibiotics/antivirals during the preceding year), recent serious or life-threatening infection within 6 months (including herpes zoster), or any current sign or symptom that may indicate an infection * Subjects who have had a splenectomy * Subjects who have had a hypersensitivity reaction to previous pneumococcal or influenza vaccination * Subjects who have a known hypersensitivity to eggs and egg products or to other components of the vaccine * Subjects with a history of Guillain-Barre syndrome * Subjects with a history of tuberculosis, active tuberculosis, positive chest x-ray for tuberculosis, or positive purified protein derivative (PPD) skin test (defined as induration of ≥5 mm). Subjects who are not candidates for PPD testing due to prior severe reaction to the PPD test or a history of PPD positivity must undergo an Elispot test instead for tuberculosis evaluation. Subjects testing positive via the PPD or having an indeterminate or positive Elispot test, or for which latent tuberculosis cannot be ruled out, may be enrolled in the study provided that they are treated (eg., isoniazid for 9 months) and that their treatment has been initiated at least 4 weeks prior to the first administration of CZP * Subjects at high risk of infection (eg., presence of leg ulcers or an indwelling urinary catheter, persistent or recurrent chest infections, bedridden or wheelchair bound subjects) * Subjects with a history of a lymphoproliferative disorder including lymphoma or signs and symptoms suggestive of lymphoproliferative disease * Subjects with known concurrent acute or chronic viral hepatitis B or C or positive hepatitis B surface antigen (HBs-Ag) or hepatitis C virus antibody (HCV-Ab) * Subjects with known human immunodeficiency virus (HIV) infection * Subjects receiving any live or attenuated vaccination within 12 weeks prior to Week 0 * Concurrent malignancy or a history of malignancy (other than carcinoma of the cervix or basal cell carcinoma successfully treated more than 5 years prior to screening) * Subjects with Class III or Class IV congestive heart failure according to the New York Heart Association (NYHA) 1964 classification criteria * Subjects with a history of, or suspected, demyelinating disease of the central nervous system (eg., multiple sclerosis or optic neuritis) * Subjects with a current or recent history of severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological or cerebral disease * Subjects with any other condition (eg., clinically significant laboratory values) which in the Investigator's judgement would make the subject unsuitable for inclusion in the study * Subjects with a history of an adverse reaction to polyethylene glycol (PEG)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6. | Baseline, End of single blind period (Week 6) |
| Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6. | Baseline, End of single blind period (Week 6) |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Subjects With no Previous Protective Pneumococcal Antibody Titers at Baseline With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6. | Baseline, End of single blind period (Week 6) |
| Percentage of Subjects With no Previous Protective Influenza Antibody Titers at Baseline With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6. | Baseline, End of single blind period (week 6) |
| Percentage of All Subjects With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6. | End of single blind period (Week 6) |
| Percentage of All Subjects Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6. | End of single blind period (Week 6) |
| Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens at Week 6 by Concomitant Methotrexate (MTX) Use. | Baseline, End of single blind period (Week 6) |
| Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens at Week 6 by Concomitant MTX Use. | Baseline, End of single blind period (Week 6) |
| Percentage of All Subjects With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6. | End of single blind period (Week 6) |
| Percentage of All Subjects Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6. | End of single blind period (Week 6) |
Countries
United States
Participant flow
Recruitment details
This study started in September of 2009 with recruitment occurring in the United States. The primary outcome completed in June 2010 and the open-label extension completed in February 2011.
Pre-assignment details
Treatment column headings reflect the treatment received in the Single-Blind (SB) period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo - Two 0.9% saline subcutaneous (sc) injections at Week 0, Week 2, and Week 4 followed by two sc injections of Open-Label (OL) CZP 200 mg at Weeks 6, 8 and 10, then one sc injection of OL CZP 200 mg every two weeks from Week 12 until last drug administration (up to Week 32). | 114 |
| Cimzia Certolizumab pegol - Two 200 mg subcutaneous (sc) injections at Week 0, Week 2, and Week 4 followed by one sc injection of Open-Label (OL) CZP 200 mg from Week 6 until last drug administration (up to Week 32). | 110 |
| Total | 224 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-Label Period | Adverse Event | 9 | 8 |
| Open-Label Period | Lack of Efficacy | 4 | 3 |
| Open-Label Period | Lost to Follow-up | 6 | 1 |
| Open-Label Period | Withdrawal by Subject | 4 | 3 |
| Single-Blind Period | Adverse Event | 1 | 1 |
| Single-Blind Period | Lack of Efficacy | 0 | 1 |
| Single-Blind Period | Lost to Follow-up | 3 | 1 |
Baseline characteristics
| Characteristic | Cimzia | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 12 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants | 102 Participants | 196 Participants |
| Age, Continuous | 53.05 years STANDARD_DEVIATION 11.78 | 52.65 years STANDARD_DEVIATION 11.12 | 52.85 years STANDARD_DEVIATION 11.42 |
| Region of Enrollment United States | 110 participants | 114 participants | 224 participants |
| Sex: Female, Male Female | 92 Participants | 87 Participants | 179 Participants |
| Sex: Female, Male Male | 18 Participants | 27 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 114 | 22 / 110 | 155 / 219 |
| serious Total, serious adverse events | 1 / 114 | 2 / 110 | 15 / 219 |
Outcome results
Primary
Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6.
Time frame: Baseline, End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 176 were in the Per Protocol Set Pneumococcal (PPSP) population (88 Placebo, 88 CZP) without baseline protective titers, and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6. | 62.5 percentage of participants |
| Cimzia | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6. | 54.5 percentage of participants |
Primary
Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6.
Time frame: Baseline, End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 169 were in the Per Protocol Set Influenza (PPSI) population (83 Placebo, 86 CZP) without baseline protective titers, and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6. | 61.4 percentage of participants |
| Cimzia | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6. | 53.5 percentage of participants |
Secondary
Percentage of All Subjects Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6.
Time frame: End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 217 were in the Full Analysis Set Pneumococcal (FASP) population (110 Placebo, 107 CZP), and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of All Subjects Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6. | 58.2 percentage of participants |
| Cimzia | Percentage of All Subjects Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens (6B, 9V, 14, 18C, 19F, and 23F) at Week 6. | 53.3 percentage of participants |
Secondary
Percentage of All Subjects Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6.
Time frame: End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 109 were in the Full Analysis Set Influenza (FASI) population (109 Placebo, 107 CZP), and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of All Subjects Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6. | 54.1 percentage of participants |
| Cimzia | Percentage of All Subjects Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens (2009/2010 Composition) at Week 6. | 50.5 percentage of participants |
Secondary
Percentage of All Subjects With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6.
Time frame: End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 216 were in the Full Analysis Set Influenza (FASI) population (109 Placebo, 107 CZP), and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of All Subjects With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6. | 77.1 percentage of participants |
| Cimzia | Percentage of All Subjects With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6. | 71.0 percentage of participants |
Secondary
Percentage of All Subjects With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6.
Time frame: End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 217 were in the Full Analysis Set Pneumococcal (FASP) population (110 Placebo, 107 CZP), and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of All Subjects With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6. | 65.5 percentage of participants |
| Cimzia | Percentage of All Subjects With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6. | 62.6 percentage of participants |
Secondary
Percentage of Subjects With no Previous Protective Influenza Antibody Titers at Baseline With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6.
Time frame: Baseline, End of single blind period (week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 169 were in the Per Protocol Set Influenza (PPSI) population (83 Placebo, 86 CZP) without baseline protective titers but with protective influenza antibody titers, and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects With no Previous Protective Influenza Antibody Titers at Baseline With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6. | 73.5 percentage of participants |
| Cimzia | Percentage of Subjects With no Previous Protective Influenza Antibody Titers at Baseline With Protective Influenza Antibody Titers (≥1:40 in ≥ 2 of 3 Influenza Antigens) at Week 6. | 64.0 percentage of participants |
Secondary
Percentage of Subjects With no Previous Protective Pneumococcal Antibody Titers at Baseline With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6.
Time frame: Baseline, End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 180 were in the Per Protocol Set Pneumococcal (PPSP) population (90 Placebo, 90 CZP) without baseline protective titers. Of these 180 subjects 150 (75 Placebo, 75 CZP) had protective pneumococcal antibody titers and are included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Subjects With no Previous Protective Pneumococcal Antibody Titers at Baseline With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6. | 57.3 percentage of participants |
| Cimzia | Percentage of Subjects With no Previous Protective Pneumococcal Antibody Titers at Baseline With Protective Pneumococcal Antibody Titers (≥1.6 µg/ml in ≥ 3 of 6 of the Pneumococcal Antigens) at Week 6. | 50.7 percentage of participants |
Secondary
Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens at Week 6 by Concomitant Methotrexate (MTX) Use.
Time frame: Baseline, End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 176 were in the Per Protocol Set Pneumococcal (PPSP) population (88 Placebo, 88 CZP) without baseline protective titers, and are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens at Week 6 by Concomitant Methotrexate (MTX) Use. | Concomitant MTX Use (n=60, 63) | 50.0 percentage of participants |
| Placebo | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens at Week 6 by Concomitant Methotrexate (MTX) Use. | No Concomitant MTX Use (n=28, 25) | 89.3 percentage of participants |
| Cimzia | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens at Week 6 by Concomitant Methotrexate (MTX) Use. | Concomitant MTX Use (n=60, 63) | 44.4 percentage of participants |
| Cimzia | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 2-fold Titer Increase in ≥ 3 of 6 Pneumococcal Antigens at Week 6 by Concomitant Methotrexate (MTX) Use. | No Concomitant MTX Use (n=28, 25) | 80.0 percentage of participants |
Secondary
Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens at Week 6 by Concomitant MTX Use.
Time frame: Baseline, End of single blind period (Week 6)
Population: Of the 224 randomized subjects (114 Placebo, 110 CZP), 169 were in the Per Protocol Set Influenza (PPSI) population (83 Placebo, 86 CZP) without baseline protective titers, and are included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens at Week 6 by Concomitant MTX Use. | No Concomitant MTX Use (n=26, 27) | 84.6 percentage of participants |
| Placebo | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens at Week 6 by Concomitant MTX Use. | Concomitant MTX Use (n=57, 59) | 50.9 percentage of participants |
| Cimzia | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens at Week 6 by Concomitant MTX Use. | Concomitant MTX Use (n=57, 59) | 45.8 percentage of participants |
| Cimzia | Percentage of Subjects Without Baseline Protective Titers Achieving a ≥ 4-fold Titer Increase in ≥ 2 of 3 Influenza Antigens at Week 6 by Concomitant MTX Use. | No Concomitant MTX Use (n=26, 27) | 70.4 percentage of participants |