Ankylosing Spondylitis
Conditions
Keywords
Ankylosing Spondylitis, Bimekizumab, AS, Certolizumab Pegol, Cimzia
Brief summary
The purpose of the study is to evaluate the efficacy and safety of bimekizumab compared to certolizumab pegol in the treatment of subjects with active ankylosing spondylitis (AS).
Interventions
DRUGBimekizumab
One bimekizumab dose will be administered.
DRUGCertolizumab pegol
Two certolizumab pegol doses will be administered. One of these doses is a loading dose.
OTHERPlacebo
Placebo will be provided to maintain the blinding.
Sponsors
UCB Biopharma SRL
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is an investigator-blind and subject-blind study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of active adult-onset ankylosing spondylitis (AS) as defined by documented radiologic evidence (X-ray) fulfilling the Modified New York criteria for AS (1984) of at least 3 months' symptom duration and age of onset \<45 years * Subject has moderate to severe active disease at the Screening Visit as defined by each of the following: 1. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score \>=4 2. Spinal pain \>=4 on a 0 to 10 numeric rating scale (NRS) (from BASDAI Item 2) * Subjects must have had an inadequate response to, have a contraindication to, or have been intolerant to at least 2 nonsteroidal anti-inflammatory drugs (NSAIDs) * Subjects taking corticosteroids must be on a maximum daily dose of \<=10mg/day oral prednisolone or equivalent * Subjects taking methotrexate (MTX; \<=25 mg/week) are allowed to continue their medication if they received a stable dose for at least 12 weeks before randomization * Subjects taking sulfasalazine (up to 3 grams/day) or hydroxychloroquine (up to 400 mg per day total) are allowed to continue their medication if started at least 12 weeks prior to randomization * Subject who has been on an anti-tumor necrosis factor alpha (TNFα) agent must have experienced an inadequate response to previous or current treatment given at an approved dose for at least 3 months or have been intolerant to at least 1 administration of an anti-TNFα agent. Subjects may not have been on more than 1 anti-TNFα agent * Subject has high-sensitive C-Reactive Protein (hsCRP) levels \>=3 mg/L at the Screening Visit * Female subjects must be postmenopausal, permanently sterilized or, if of childbearing potential, must be willing to use a highly effective method of contraception up till 20 weeks after last administration of investigational medicinal product (IMP) * Male subjects with a partner of childbearing potential must be willing to use a condom when sexually active, up till 20 weeks after the last administration of IMP
Exclusion criteria
* Subject has received previous or current biological treatment other than TNFα inhibitor treatment * Subjects with a total ankylosis of the spine, or a diagnosis of any other inflammatory arthritis eg, rheumatoid arthritis (RA), sarcoidosis, systemic lupus erythematosus, or reactive arthritis * Subjects with any current sign or symptom that may indicate an active infection (except for the common cold) * Subject has received previous or current biological treatment other than TNFα inhibitor treatment * Subject has chronic, recurrent, recent serious / life-threatening or current infection, as defined in the protocol * Subject has history of certain atypical infections, viral hepatitides, human immunodeficiency virus (HIV) infection, tuberculosis, as defined in the protocol * Subjects receiving any live vaccination within the 8 weeks prior to Baseline * Subjects with known tuberculosis (TB) infection, at high risk of acquiring TB infection, with latent TB infection or current or history of nontuberculous mycobacteria (NTMB) infection * Subject has immunosuppressive condition or treatment, recent history of malignancy (some exceptions) or demyelinating disease * Subjects with concurrent malignancy or a history of malignancy during the past 5 years will be excluded, with following exceptions that may be included: 1. \<= 3 excised or ablated basal cell carcinomas of the skin 2. One squamous cell carcinoma of the skin (stage T1 maximum) successfully excised, or ablated only (other treatments, ie, chemotherapy, do not apply), with no signs of recurrence or metastases for more than 2 years prior to Screening 3. Actinic keratosis (-es) 4. Squamous cell carcinoma-in-situ of the skin successfully excised, or ablated, more than 6 months prior to Screening * Subject has history of psychiatric disorder, including suicidality (as defined in the protocol * Subject has major abnormalities on laboratory testing, as defined in the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12 | From Baseline to Week 12 | ASDAS was calculated as the sum of the results from the following components: 0.121xTotal spinal pain (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 result), 0.058xDuration of morning stiffness (BASDAI Question 6 result), 0.110xPGADA, 0.073xPeripheral pain/swelling (BASDAI Question 3 result), 0.579x(natural logarithm of the CRP \[mg/L\] + 1), Spinal pain, PGADA, duration of morning stiffness, peripheral pain/swelling were all assessed on a numerical scale (0 to 10 units). There is a minimum score of 0.980 for ASDAS (as a fixed value of 2 was assumed for values of hs-CRP below the LLOQ), but no defined upper score. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. Posterior means and 95% credible intervals in each group are presented. |
| Number of Participants With Adverse Events (AE) During the Study Conduct | From Baseline until Safety Follow-Up Visit (up to Week 64) | An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A treatment-emergent adverse event (TEAE) was defined as any AE with a start date/time at the time of or after the first dose of IMP up until 140 days after the last dose of IMP. |
| Number of Participants With Serious Adverse Events (SAEs) During the Study Conduct | From Baseline until Safety Follow-Up Visit (up to Week 64) | An SAE was any untoward medical occurrence that at any dose: - Resulted in death - Is life-threatening - Required in patient hospitalisation or prolongation of existing hospitalisation - Is a congenital anomaly or birth defect - Is an infection that requires treatment with parenteral antibiotics - Other important medical events which based on medical or scientific judgement may jeopardised the participants, or may require medical or surgical intervention to prevent any of the above. A TEAE was defined as any AE with a start date/time at the time of or after the first dose of IMP up until 140 days after the last dose of IMP. |
| Number of Participants Who Withdrew Due to an Adverse Event (AE) During the Study Conduct | From Baseline until Safety Follow-Up Visit (up to Week 64) | An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE was defined as any AE with a start date/time at the time of or after the first dose of IMP up until 140 days after the last dose of IMP. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Ankylosing Spondylitis Disease Activity Score - Inactive Disease (ASDAS-ID) at Week 12 | Week 12 | ASDAS-ID was defined by ASDAS \< 1.3. ASDAS was calculated as the sum of the results from the following components: 0.121xTotal spinal pain (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 result), 0.058xDuration of morning stiffness (BASDAI Question 6 result), 0.110xPGADA, 0.073xPeripheral pain/swelling (BASDAI Question 3 result), 0.579x(natural logarithm of the CRP \[mg/L\] + 1), Spinal pain, PGADA, duration of morning stiffness, peripheral pain/swelling were all assessed on a numerical scale (0 to 10 units). There is a minimum score of 0.980 for ASDAS (as a fixed value of 2 was assumed for values of hs-CRP below the LLOQ), but no defined upper score. |
| Number of Participants With Ankylosing Spondylitis Disease Activity Score-Major Improvement (ASDAS-MI) at Week 12 | Baseline, Week 12 | ASDAS-MI was defined by a reduction (improvement) from Baseline in ASDAS \>=2 units. ASDAS was calculated as the sum of the results from the following components: 0.121xTotal spinal pain (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 result), 0.058xDuration of morning stiffness (BASDAI Question 6 result), 0.110xPGADA, 0.073xPeripheral pain/swelling (BASDAI Question 3 result), 0.579x(natural logarithm of the CRP \[mg/L\] + 1), Spinal pain, PGADA, duration of morning stiffness, peripheral pain/swelling were all assessed on a numerical scale (0 to 10 units). There is a minimum score of 0.980 for ASDAS (as a fixed value of 2 was assumed for values of hs-CRP below the LLOQ), but no defined upper score. |
Countries
Czechia, Germany, Greece, Moldova, Netherlands, Poland, Russia, United States
Participant flow
Recruitment details
The study started to enroll study participants in October 2017 and concluded in May 2020.
Pre-assignment details
The Participant Flow refers to the Randomized Set (RS).
Participants by arm
| Arm | Count |
|---|---|
| Certolizumab Pegol Participants received certolizumab pegol (CZP) 400 milligrams (mg) subcutaneously (sc) every 2 weeks (Q2W) at Weeks 0, 2, and 4 (loading dose) followed by CZP 200 mg sc Q2W in Weeks 6 to 10 and 400 mg every 4 weeks (Q4W) from Week 12 to Week 44. | 25 |
| Bimekizumab Participants received bimekizumab (BKZ) 160 mg sc Q2W from Week 0 through Week 10 and 320 mg sc Q4W from Week 12 to Week 44. In addition, participants received placebo injection to maintain the blind for the CZP loading dose at Baseline, Week 2 and Week 4. | 51 |
| Total Title | 76 |
| Total | 152 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Participant was unable to attend clinic visit | 0 | 1 |
Baseline characteristics
| Characteristic | Certolizumab Pegol | Bimekizumab | Total Title |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 47 Participants | 72 Participants |
| Age, Continuous | 39.7 years STANDARD_DEVIATION 8.2 | 40.3 years STANDARD_DEVIATION 12.5 | 40.1 years STANDARD_DEVIATION 11.2 |
| Race/Ethnicity, Customized Not Hispanic or Latino | 25 Participants | 51 Participants | 76 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 51 Participants | 76 Participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 21 Participants | 44 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 0 / 51 |
| other Total, other adverse events | 16 / 25 | 27 / 51 |
| serious Total, serious adverse events | 3 / 25 | 5 / 51 |
Outcome results
Primary
Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12
ASDAS was calculated as the sum of the results from the following components: 0.121xTotal spinal pain (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 result), 0.058xDuration of morning stiffness (BASDAI Question 6 result), 0.110xPGADA, 0.073xPeripheral pain/swelling (BASDAI Question 3 result), 0.579x(natural logarithm of the CRP \[mg/L\] + 1), Spinal pain, PGADA, duration of morning stiffness, peripheral pain/swelling were all assessed on a numerical scale (0 to 10 units). There is a minimum score of 0.980 for ASDAS (as a fixed value of 2 was assumed for values of hs-CRP below the LLOQ), but no defined upper score. The change from Baseline is calculated, a negative value indicating improvement and a positive value worsening. Posterior means and 95% credible intervals in each group are presented.
Time frame: From Baseline to Week 12
Population: Per Protocol Set (PPS) consisted of all study participants in the Full Analysis Set who had no important protocol deviation affecting the primary efficacy variable. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Certolizumab Pegol (PPS) | Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12 | -1.83 scores on a scale |
| Bimekizumab (PPS) | Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12 | -2.06 scores on a scale |
Comparison: Results were based on a complete case (ie, data as observed) Bayesian linear model with the change from Baseline in ASDAS as the independent variable. Treatment was included as a predictor in the model and Baseline ASDAS as a covariate. The mean posterior difference and 95% credible interval were presented for the BKZ vs CZP comparison.95% CI: [-0.14, 0.6]Regression, Linear
Comparison: Results were based on a complete case (ie, data as observed) Bayesian linear model with the change from Baseline in ASDAS as the independent variable. Treatment was included as a predictor in the model and Baseline ASDAS as a covariate. Pr\[Diff\>0%\](%) refers to the probability that the mean change from Baseline in ASDAS in the BKZ group was greater than the mean change from Baseline in ASDAS in the CZP group.Regression, Linear
Primary
Number of Participants Who Withdrew Due to an Adverse Event (AE) During the Study Conduct
An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE was defined as any AE with a start date/time at the time of or after the first dose of IMP up until 140 days after the last dose of IMP.
Time frame: From Baseline until Safety Follow-Up Visit (up to Week 64)
Population: Safety Set (SS) consisted of all randomized study participants who received at least 1 dose (full or partial) of the IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Certolizumab Pegol (PPS) | Number of Participants Who Withdrew Due to an Adverse Event (AE) During the Study Conduct | 3 Participants |
| Bimekizumab (PPS) | Number of Participants Who Withdrew Due to an Adverse Event (AE) During the Study Conduct | 3 Participants |
Primary
Number of Participants With Adverse Events (AE) During the Study Conduct
An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A treatment-emergent adverse event (TEAE) was defined as any AE with a start date/time at the time of or after the first dose of IMP up until 140 days after the last dose of IMP.
Time frame: From Baseline until Safety Follow-Up Visit (up to Week 64)
Population: Safety Set (SS) consisted of all randomized study participants who received at least 1 dose (full or partial) of the IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Certolizumab Pegol (PPS) | Number of Participants With Adverse Events (AE) During the Study Conduct | 19 Participants |
| Bimekizumab (PPS) | Number of Participants With Adverse Events (AE) During the Study Conduct | 42 Participants |
Primary
Number of Participants With Serious Adverse Events (SAEs) During the Study Conduct
An SAE was any untoward medical occurrence that at any dose: - Resulted in death - Is life-threatening - Required in patient hospitalisation or prolongation of existing hospitalisation - Is a congenital anomaly or birth defect - Is an infection that requires treatment with parenteral antibiotics - Other important medical events which based on medical or scientific judgement may jeopardised the participants, or may require medical or surgical intervention to prevent any of the above. A TEAE was defined as any AE with a start date/time at the time of or after the first dose of IMP up until 140 days after the last dose of IMP.
Time frame: From Baseline until Safety Follow-Up Visit (up to Week 64)
Population: Safety Set (SS) consisted of all randomized study participants who received at least 1 dose (full or partial) of the IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Certolizumab Pegol (PPS) | Number of Participants With Serious Adverse Events (SAEs) During the Study Conduct | 3 Participants |
| Bimekizumab (PPS) | Number of Participants With Serious Adverse Events (SAEs) During the Study Conduct | 5 Participants |
Secondary
Number of Participants With Ankylosing Spondylitis Disease Activity Score - Inactive Disease (ASDAS-ID) at Week 12
ASDAS-ID was defined by ASDAS \< 1.3. ASDAS was calculated as the sum of the results from the following components: 0.121xTotal spinal pain (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 result), 0.058xDuration of morning stiffness (BASDAI Question 6 result), 0.110xPGADA, 0.073xPeripheral pain/swelling (BASDAI Question 3 result), 0.579x(natural logarithm of the CRP \[mg/L\] + 1), Spinal pain, PGADA, duration of morning stiffness, peripheral pain/swelling were all assessed on a numerical scale (0 to 10 units). There is a minimum score of 0.980 for ASDAS (as a fixed value of 2 was assumed for values of hs-CRP below the LLOQ), but no defined upper score.
Time frame: Week 12
Population: Per-Protocol Set (PPS) consisted of all study participants in the Full Analysis Set who had no important protocol deviation affecting the primary efficacy variable. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Certolizumab Pegol (PPS) | Number of Participants With Ankylosing Spondylitis Disease Activity Score - Inactive Disease (ASDAS-ID) at Week 12 | 5 Participants |
| Bimekizumab (PPS) | Number of Participants With Ankylosing Spondylitis Disease Activity Score - Inactive Disease (ASDAS-ID) at Week 12 | 11 Participants |
Secondary
Number of Participants With Ankylosing Spondylitis Disease Activity Score-Major Improvement (ASDAS-MI) at Week 12
ASDAS-MI was defined by a reduction (improvement) from Baseline in ASDAS \>=2 units. ASDAS was calculated as the sum of the results from the following components: 0.121xTotal spinal pain (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Question 2 result), 0.058xDuration of morning stiffness (BASDAI Question 6 result), 0.110xPGADA, 0.073xPeripheral pain/swelling (BASDAI Question 3 result), 0.579x(natural logarithm of the CRP \[mg/L\] + 1), Spinal pain, PGADA, duration of morning stiffness, peripheral pain/swelling were all assessed on a numerical scale (0 to 10 units). There is a minimum score of 0.980 for ASDAS (as a fixed value of 2 was assumed for values of hs-CRP below the LLOQ), but no defined upper score.
Time frame: Baseline, Week 12
Population: Per-Protocol Set (PPS) consisted of all study participants in the Full Analysis Set who had no important protocol deviation affecting the primary efficacy variable. Here, Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Certolizumab Pegol (PPS) | Number of Participants With Ankylosing Spondylitis Disease Activity Score-Major Improvement (ASDAS-MI) at Week 12 | 11 Participants |
| Bimekizumab (PPS) | Number of Participants With Ankylosing Spondylitis Disease Activity Score-Major Improvement (ASDAS-MI) at Week 12 | 28 Participants |