Ankylosing Spondyloarthritis
Conditions
Keywords
Ankylosing Spondyloarthritis, Axial spondyloarthritis
Brief summary
The purpose of this trial is to demonstrate the clinical efficacy at week 16; and to demonstrate safety and tolerability of secukinumab compared to placebo in patients with ankylosing spondylitis at week 16 and long term safety up to Week 52.
Detailed description
This multicenter study used a randomized, double-blind, placebo-controlled, parallel-group design. A screening period running up to 10 weeks before randomization was used to assess eligibility, followed by 52 weeks of treatment. At baseline, subjects were randomized to one of the two treatment groups: * Group 1: 300 subjects, secukinumab 150 mg (1 mL, 150 mg/mL) s.c. pre-filled syringes (PFS) at BSL, Weeks 1, 2, and 3, followed by administration every four weeks starting at Week 4 * Group 2: 150 subjects, placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, 4, 8, and 12, followed by secukinumab 150 mg (1 mL, 150 mg/mL) administration every four weeks starting at Week 16 The subjects were stratified at randomization according to the region (China and non-China). Approximately 70% of randomized subjects were from China (327 Chinese subjects) in order to evaluate the efficacy and safety in this subject population. No more than 30% TNFα inhibitor inadequate responders (TNF-IR) subjects were to be enrolled in the study. Starting at Week 16, all subjects switched to open-label secukinumab 150 mg, including all placebo subjects; however, all subjects and investigators/site staff remained blinded to the original randomized treatment group assignment (150 mg vs placebo). Study treatment continued up to Week 48. An end of treatment visit was done 4 weeks after last study treatment administration and a post treatment follow-up visit was done 12 weeks after last study treatment administration for all subjects (regardless of whether they completed the entire study as planned or discontinued prematurely). Subjects were instructed in detail how to self-administer the s.c. injection using PFS. Each injection was administered into an appropriate injection site of the body (thighs, arms, or abdomen). All injections were performed at the study site. Site personnel administered the injections to subjects who were not able to, or felt insecure to self-administer. Rescue medication was not allowed until Week 20. However, subjects who were deemed by the investigator not to be benefiting from the study treatment based on safety and efficacy assessments or for any reason of their own accord were free to discontinue participation in the study at any time.
Interventions
DRUGSecukinumab
Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly All Subjects received blinded treatment weekly starting at baseline, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until Week 16. At Week 16, Group 1 patients continued using secukinumab 150 mg and Group 2 patients started receiving secukinumab 150 mg dosing every four weeks. Treatment was provided open-label from Week 16 onward, as all patients took 150 mg s.c. every 4 weeks; however, subjects, investigators, and site staff remained blinded to initial randomized group assignment.
DRUGPlacebo
Induction: 4x placebo s.c. weekly Maintenance: placebo s.c. monthly
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Male or non-pregnant, non-lactating female patients at least 18 years of age Diagnosis of moderate to severe AS with prior documented radiologic evidence (x-ray or radiologist's report) fulfilling the Modified New York criteria for AS: * Active AS assessed by BASDAI ≥4 (0-10) at Baseline * Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline * Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline Patients should have had inadequate response or failure to respond to at least 2 NSAIDs at an approved dose for a minimum of 4 weeks in total and a minimum of 2 weeks for each NSAID prior to randomization, or less than 4 weeks if therapy had to be withdrawn due to intolerance, toxicity or contraindications Patients who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part of their AS therapy are required to be on a stable dose for at least 2 weeks before randomisation Patients who have been on a TNFα inhibitor (not more than one) must have experienced an inadequate response to previous or current treatment given at an approved dose for at least 3 months prior to randomization or have been intolerant to at least one administration of an anti-TNFα agent
Exclusion criteria
* Chest X-ray or MRI with evidence of ongoing infectious or malignant process * Patients taking high potency opioid analgesics * Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or IL-17 receptor * Pregnant or nursing (lactating) women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Participants Who Achieve an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria) | Week 16 | ASAS20 response is defined as an improvement of ≥20% and ≥1 units on a scale of 10 in at least three of the four ASAS main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in hsCRP Over Time | Change from baseline to Week 16. The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes. | hsCRP is measured as a marker of inflammation from blood samples during the study The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS. |
| Percentage of Participants Who Achieve an ASAS 5/6 at Week 16 | Week 16: The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes. | The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six domains The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS. |
| Participants With BASDAI Response at 16 Weeks | The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes. | The BASDAI or Bath Ankylosing Spondylitis Disease Activity Index consists of a 0 through 10 scale (0 being no problem and 10 being the worst problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 5 major symptoms of AS The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS. |
| The Proportion of Participants Who Achieve an ASAS40 Response | The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes. | ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at least three of the four ASAS main domains and no worsening at all in the remaining domain The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS. |
| Change in ASQoL Score Over Time | change from baseline to Week 16 | The Ankylosing Spondylitis Quality of Life (ASQoL) is an instrument to assess health-related quality of life among adult patients with Ankylosing Spondylitis. Each statement on the ASQoL is given a score of 1 or 0. A score of 1 is given where the item is affirmed, indicating adverse QoL. All item scores are summed to give a total score or index. Scores can range from 0 (good QoL) to 18 (poor QoL). |
| The Proportion of Patients Who Achieve an ASAS Partial Remission | Week 16 | The The Assessment in SpondyloArthritis International Society (ASAS) partial remission criteria are defined as a value not above 2 units in each of the four main domains on a scale of 10 The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS. |
| Change in Short Form (36) - PCS Responders (Improvement of >= 2.5 Points) at Week 16 | The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes. | The Physical Component Summary (PCS) SF-36 is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS. |
Countries
China, Czechia, South Korea, United Kingdom
Participant flow
Recruitment details
The majority of subjects completed 52 weeks of treatment. After Week 16 all participants originally assigned to placebo switched to AIN457 150 mg s.c. Four out of the 153 assigned to the placebo group discontinued before Week 16.
Pre-assignment details
All patients independent of completer status were asked to enter follow up whenever they exited the study no matter at what time in their participation. Moreover, not all participants who completed Week 52 entered the follow up period and some did not complete follow-up. Therefore, the number of participants who started the follow-up period is not equal to the number of participants who completed the previous period.
Participants by arm
| Arm | Count |
|---|---|
| Secukinumab AIN457 150 mg s.c. | 305 |
| Placebo Placebo s.c. | 153 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| COMPLETED POST-TREATMENT FOLLOW UP | Lost to Follow-up | 0 | 1 |
| COMPLETED POST-TREATMENT FOLLOW UP | Physician Decision | 1 | 0 |
| COMPLETED POST-TREATMENT FOLLOW UP | Pregnancy | 1 | 0 |
| COMPLETED POST-TREATMENT FOLLOW UP | Protocol Violation | 0 | 1 |
| COMPLETED POST-TREATMENT FOLLOW UP | Withdrawal by Subject | 2 | 3 |
| COMPLETED WEEK 52 | Adverse Event | 9 | 2 |
| COMPLETED WEEK 52 | Lack of Efficacy | 2 | 3 |
| COMPLETED WEEK 52 | Lost to Follow-up | 0 | 1 |
| COMPLETED WEEK 52 | Physician Decision | 1 | 1 |
| COMPLETED WEEK 52 | Pregnancy | 2 | 0 |
| COMPLETED WEEK 52 | Technical problems | 1 | 0 |
| COMPLETED WEEK 52 | Withdrawal by Subject | 12 | 4 |
Baseline characteristics
| Characteristic | Secukinumab | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 303 Participants | 152 Participants | 455 Participants |
| Race/Ethnicity, Customized Asian | 239 participants | 130 participants | 369 participants |
| Race/Ethnicity, Customized Other | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 64 participants | 23 participants | 87 participants |
| Sex: Female, Male Female | 53 Participants | 21 Participants | 74 Participants |
| Sex: Female, Male Male | 252 Participants | 132 Participants | 384 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 453 | 0 / 153 |
| other Total, other adverse events | 282 / 453 | 60 / 153 |
| serious Total, serious adverse events | 33 / 453 | 3 / 153 |
Outcome results
Primary
The Proportion of Participants Who Achieve an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria)
ASAS20 response is defined as an improvement of ≥20% and ≥1 units on a scale of 10 in at least three of the four ASAS main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain
Time frame: Week 16
Population: Full Analysis Set (FAS) was comprised of all subjects from the randomized set to whom study treatment had been assigned. Following the intent-to-treat principle, subjects were evaluated according to the treatment assigned to at randomization, but actual stratum, if stratified randomization was used.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Secukinumab | The Proportion of Participants Who Achieve an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria) | 178 Participants |
| Placebo | The Proportion of Participants Who Achieve an ASAS 20 Response (Assessment of SpondyloArthritis International Society Criteria) | 56 Participants |
p-value: <0.000195% CI: [1.65, 3.69]Regression, Logistic
Secondary
Change in ASQoL Score Over Time
The Ankylosing Spondylitis Quality of Life (ASQoL) is an instrument to assess health-related quality of life among adult patients with Ankylosing Spondylitis. Each statement on the ASQoL is given a score of 1 or 0. A score of 1 is given where the item is affirmed, indicating adverse QoL. All item scores are summed to give a total score or index. Scores can range from 0 (good QoL) to 18 (poor QoL).
Time frame: change from baseline to Week 16
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Secukinumab | Change in ASQoL Score Over Time | -4.6 scores | Standard Deviation 4.98 |
| Placebo | Change in ASQoL Score Over Time | -2.6 scores | Standard Deviation 4.28 |
Secondary
Change in hsCRP Over Time
hsCRP is measured as a marker of inflammation from blood samples during the study The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.
Time frame: Change from baseline to Week 16. The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Secukinumab | Change in hsCRP Over Time | -11.78 mg/l | Standard Deviation 22.919 |
| Placebo | Change in hsCRP Over Time | -0.79 mg/l | Standard Deviation 20.023 |
Secondary
Change in Short Form (36) - PCS Responders (Improvement of >= 2.5 Points) at Week 16
The Physical Component Summary (PCS) SF-36 is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.
Time frame: The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Change in Short Form (36) - PCS Responders (Improvement of >= 2.5 Points) at Week 16 | 71.8 percent of participants |
| Placebo | Change in Short Form (36) - PCS Responders (Improvement of >= 2.5 Points) at Week 16 | 61.1 percent of participants |
Secondary
Participants With BASDAI Response at 16 Weeks
The BASDAI or Bath Ankylosing Spondylitis Disease Activity Index consists of a 0 through 10 scale (0 being no problem and 10 being the worst problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 5 major symptoms of AS The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.
Time frame: The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Participants With BASDAI Response at 16 Weeks | 41.7 percent of participants |
| Placebo | Participants With BASDAI Response at 16 Weeks | 22.6 percent of participants |
Secondary
Percentage of Participants Who Achieve an ASAS 5/6 at Week 16
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six domains The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.
Time frame: Week 16: The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | Percentage of Participants Who Achieve an ASAS 5/6 at Week 16 | 50.5 percentage of participants |
| Placebo | Percentage of Participants Who Achieve an ASAS 5/6 at Week 16 | 19.2 percentage of participants |
Secondary
The Proportion of Participants Who Achieve an ASAS40 Response
ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at least three of the four ASAS main domains and no worsening at all in the remaining domain The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.
Time frame: The secondary outcome analysis occurred only at Week 16. Thus, while data were collected beyond week 16, they were not part of the secondary outcomes.
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Secukinumab | The Proportion of Participants Who Achieve an ASAS40 Response | 138 Participants |
| Placebo | The Proportion of Participants Who Achieve an ASAS40 Response | 27 Participants |
Secondary
The Proportion of Patients Who Achieve an ASAS Partial Remission
The The Assessment in SpondyloArthritis International Society (ASAS) partial remission criteria are defined as a value not above 2 units in each of the four main domains on a scale of 10 The number analyzed for some of continuous outcome variables are the number of participants for whom the specific outcome data were available. Thus the number for these variables differs from the FAS.
Time frame: Week 16
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Secukinumab | The Proportion of Patients Who Achieve an ASAS Partial Remission | 17.7 percent of participants |
| Placebo | The Proportion of Patients Who Achieve an ASAS Partial Remission | 7.5 percent of participants |