Ankylosing Spondylitis
Conditions
Keywords
Active axSpA, Axial spondyloarthritis, non-radiographic-axSpA, nr-axSpA, ankylosing spondylitis, AS, inflammatory back pain, sacroiliitis
Brief summary
The purpose of this global study was to demonstrate the efficacy, safety, and tolerability of an intravenous (i.v.) regimen of secukinumab compared to placebo in participants with active ankylosing spondylitis (AS) or non-radiographic axial spondyloarthritis (nr-axSpA ) at Week 16 despite current or previous non-steroidal anti inflammatory drugs (NSAID), disease-modifying antirheumatic drugs (DMARD) and/or anti Tumor Necrosis Factor (TNF) therapy. In addition, to further support efficacy and safety of an i.v. regimen, data was collected for up to 52 weeks of treatment.
Detailed description
This multicenter study used a randomized, double-blind, placebo-controlled, parallel-group design to study the efficacy, safety, and tolerability of treatment with intravenous secukinumab (initial dose of 6 mg/kg followed thereafter with 3 mg/kg administered every four weeks starting at Week 4) in subjects with active axial spondyloarthritis (axSpA). The study population consisted of active of 413 participants with AS and 113 participants with active nr-axSpA. This study consisted of 4 periods totaling up to 70 weeks: the screening period (up to 10 weeks), the treatment period 1 (total duration of 16 weeks), treatment period 2 (total duration of 36 weeks) followed by the safety follow up period of 8 weeks after the end of treatment visit (at Week 60) regardless of whether participant completed the study as planned or discontinued prematurely. At baseline, participants were randomized to one of the two treatment groups and stratified to disease condition (AS or nr-axSPa): * Group 1: secukinumab 6 mg/kg i.v.) at baseline and which was followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52) at clinic visits * Group 2: i.v. placebo at baseline, Weeks 4, 8, and 12 and switched to secukinumab 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52) at clinic visits Although study treatment was open label secukinumab i.v. starting at Week 16, all subjects and investigators/site staff remained blinded to original treatment assignment to ensure unbiased efficacy and safety assessments for the remainder of the study. This study enrolled participants with active disease despite current or previous NSAIDs, conventional DMARDs and/or TNF inhibitor therapy or intolerance to these therapies. The regular assessment of disease activity ensured that subjects who experienced worsening of disease in any of the treatment groups could exit the study at any time upon their own accord or based on the advice of the investigator. A temporary pause of study recruitment only was implemented from 09-Apr-2020 to 11-May-2020, due to the COVID-19 pandemic, but not for study visits, assessments or other conduct of the study.
Interventions
DRUGSecukinumab
The subjects will receive secukinumab 6 mg/kg i.v. at randomization (Baseline (BSL) visit), followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52)
DRUGPlacebo
The subjects will receive i.v. placebo at randomization (BSL visit), Weeks 4, 8, and 12 , followed by the administration of secukinumab 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind, randomized treatment trial. Subjects, investigators, investigator staff and persons performing the assessments, will remain blind to the identity of the treatment from the time of randomization until database lock, using the following methods: (1) Randomization data are kept strictly confidential until the time of unblinding and will not be accessible by anyone else involved in the study with the exception of the bioanalyst, (2) the identity of the treatments will be concealed by the use of study treatment in form of vials, filled with secukinumab or placebo that are identical in appearance.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria: 1. Subject must be able to understand and communicate with the investigator, comply with the requirements of the study. and must give written, signed and dated informed consent before any study assessment is performed 2. Male and non-pregnant, non-lactating female patients ≥ 18 years of age 3. Diagnosis of axSpA according to ASAS criteria 1. Inflammatory back pain for at least 6 months 2. Onset before 45 years of age 4. For subjects with AS: Diagnosis of AS with prior documented radiologic evidence (x-ray or radiologist's report) fulfilling the Modified New York criteria for AS 5. For subjects with nr-axSpA: X-ray of SIJ negative (centrally read) for AS by Modified NY criteria AND 1. Sacroiliitis on MRI (centrally read) with ≥ 1 SpA feature OR HLA-B-27 positive with ≥2 SpA features AND 2. Objective signs of inflammation at screening, evident by either MRI with SIJ inflammation (centrally read) AND / OR hsCRP \> ULN (as defined by the central lab) 6. Active axial SpA assessed by BASDAI ≥4 cm (0-10 cm) at Baseline 7. Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline 8. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline 9. Subjects 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 10. Subjects who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part of their AS or nr-axSpA therapy are required to be on a stable dose for at least 2 weeks before randomization 11. Subjects who are intolerant or have been inadequate responders to a TNF inhibitor (not more than one) will be allowed to enter into the study (not more than 20% per group). They must have experienced an inadequate response to previous or current treatment at an approved dose for at least 3 months prior to randomization, or have been intolerant to at least one administration of an anti-TNF agent. These subjects will undergo an appropriate wash-out period prior to randomization, if required 1. 4 weeks for Enbrel® (etanercept) - with a terminal half-life of 102 ± 30 hours 2. 8 weeks for Remicade® (infliximab) - with a terminal half-life of 8.0-9.5 days 3. 10 weeks for Humira® (adalimumab) - with a terminal half-life of 10-20 days (average 2 weeks) 4. 10 weeks for Simponi® (golimumab) - with a terminal half-life of 11-14 days 5. 10 weeks for Cimzia® (certolizumab) - with a terminal half-life of 14 days 12. Subjects taking methotrexate (MTX) (≤ 25 mg/week ) or sulfasalazine (≤ 3 g/day) are allowed to continue their medication and must have taken it for at least 3 months and have to be on a stable dose for at least 4 weeks prior to randomization. Subjects on MTX must be on folic acid supplementation before randomization 13. Subjects who are on a conventional DMARD other than MTX or sulfasalazine must discontinue the DMARD 4 weeks prior to randomization, except for leflunomide, which must be be discontinued 8 weeks prior to randomization, unless a cholestyramine washout has been performed 14. Subjects taking systemic corticosteroids must be on a stable dose of ≤10 mg/day prednisone or equivalent for at least 2 weeks before randomization
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study 1. Subjects with total ankylosis of the spine 2. Chest x-ray or MRI with evidence of ongoing infectious or malignant process obtained within 3 months of screening and evaluated by a qualified physician 3. Subjects taking moderate and high potency opioid analgesics (e.g. methadone, hydromorphone, morphine) 4. Presence of significant medical problems which at investigator's discretion, will prevent the subject from participating in the study, including but not limited to the following: Subjects with severely reduced kidney function (estimated glomerular filtration rate (eGFR) \<29 ml/min/1.73m2), history of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum creatinine level exceeding 1.5 mg/dl (132.6 μmol/L) 5. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before Randomization 6. Underlying conditions (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in the opinion of the investigator significantly immunocompromises the subject and/or places the subject at unacceptable risk for receiving an immunomodulatory therapy 7. Any medical or psychiatric condition which, in the Investigator's opinion, would preclude the participant from adhering to the protocol or completing the study per protocol 8. Active systemic infections during the last two weeks (exception: common cold) prior to randomization or any infection that reoccurs on a regular basis 9. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined by either a positive purified protein derivative (PPD) skin test (the size of induration will be measured after 48-72 hours, and a positive result is defined as an induration of ≥ 5 mm or according to local practice/guidelines) or a positive QuantiFERON TB-Gold test as indicated in the assessment schedule in Table 8-1. Subjects with a positive test may participate in the study if further work up (according to local practice/guidelines) establishes conclusively that the subject has no evidence of active tuberculosis. If presence of latent tuberculosis is established, then treatment according to local country guidelines must have been initiated 10. Past medical history of infection with HIV or hepatitis B prior to randomization or active infection or on treatment for Hepatitis C at randomization 11. History of lymphoproliferative disease or any known malignancy, or history of malignancy of any organ system treated or untreated within the past 5 years, regardless of whether there is evidence of local recurrence or metastases (except for skin Bowen's disease, or basal cell carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed) 12. Use or planned use of prohibited concomitant medication (see Section 6.2.2) 13. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor tolerability or lack of access to veins) 14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test 15. History or evidence of ongoing alcohol or drug abuse, within the last six months before randomization 16. Screening total WBC count \<3,000/μl, or platelets \<100,000/μl or neutrophils \<1,500/μl or hemoglobin \<8.5 g/dl (85 g/L) 17. History of clinically significant liver disease or liver injury indicated by abnormal liver function tests, such as SGOT (AST), SGPT (ALT), alkaline phosphatase and serum bilirubin. The investigator should be guided by the following criteria: * Any single parameter may not exceed 2 x the upper limit of normal (ULN). A single parameter elevated up to and including 2 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to randomization, to rule-out laboratory error. * If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. In any case, serum bilirubin should not exceed the value of 1.6 mg/dL (27 µmol/L) 18. Significant medical problems or diseases, including but not limited to the following: uncontrolled hypertension (≥160/95 mmHg), congestive heart failure (New York Heart Association status of class III or IV), uncontrolled diabetes, or very poor functional status precluding ability to perform self-care 19. Plans for administration of live vaccines during the study period or within 6 weeks prior to randomization 20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during the entire study or longer if required by locally approved prescribing information (e.g., 20 weeks in EU). Effective contraception methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject * Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal suppository * Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception * Placement of an intrauterine device or intrauterine system In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential. 21. Active ongoing inflammatory diseases other than axSpA that might confound the evaluation of the benefits of secukinumab therapy, including inflammatory bowel disease or uveitis 22. Current severe progressive or uncontrolled disease which in the judgment of the clinical investigator renders the subject unsuitable for the trial 23. Use of other investigational drugs at the time of enrollment, or within 5 half- lives of enrollment, or within 4 weeks until the expected pharmacodynamic effect has returned to baseline, whichever is longer; or longer if required by local regulations 24. History of hypersensitivity to any of the study drug constituents 25. Previous exposure to secukinumab (AIN457) or any other biologic drug directly targeting IL-17 or the IL-17 receptor 26. Previous treatment with any cell-depleting therapies including but not limited to anti-CD20 or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria) | Baseline to Week 16 | ASAS40 is ≥ 40% and an absolute improvement from baseline of ≥20 units (range 0-100) in ≥ 3 of the following 4 domains: back pain \[10 cm visual analogue scale (VAS)\], patient global assessment of disease activity (10 cm VAS), physical function (BASFI; range 0-100) and inflammation (mean score of items 5 and 6 of the BASDAI; both 10 cm VAS) without any worsening in the remaining domain. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline in Total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | Baseline to Week 16 | BASDAI consists of a 0 through 10 scale (0 indicating no problem and 10 indicating the worst problem, captured as a continuous VAS), which was used to answer six questions pertaining to the five major symptoms of AS: fatigue, spinal pain, peripheral joint pain / swelling,, areas of localized tenderness (enthesitis, or inflammation of tendons and ligaments), morning stiffness duration, morning stiffness severity. To give each symptom equal weight, the mean of the two scores relating to morning stiffness is taken into account (questions 5 and 6). The resulting 0 to 10 score is added to the scores for questions 1 through 4. The resulting 0 to 50 score is divided by 5 to give a final 0 10 BASDAI score. |
| Percentage of Participants Who Achieved an ASAS 5/6 (Assessment of Spondylarthritis International Society Criteria) | Baseline to Week 16 | The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six domains. A higher score on the VAS signifies higher severity. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). |
| The Change From Baseline in Total Bath Ankylosing Spondylitis Functional Index (BASFI) | Baseline to Week 16 | The BASFI is a set of 10 questions designed to determine the degree of functional limitation in subjects with AS. The questions were chosen on the basis of predominant input from subjects with AS. The first eight questions consider activities related to functional anatomy. The final two questions assess the subjects' ability to cope with everyday life. A 0-10 scale (captured as a continuous VAS) is used to answer the questions. The BASFI score is the mean of the ten scales - a value between 0 and 10. |
| The Change From Baseline in Short Form-36 Physical Component Summary (SF-36 PCS) | Baseline to Week 16 | The Short Form-36 Physical Component Summary (SF-36 PCS) is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of eight subscales (domains) that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role- Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The eight domains are based on a scale from 0-100 while PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. Higher scores indicate a higher level of functioning. A positive change from baseline score indicates an improvement. |
| The Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQol) | Baseline to Week 16 | The ASQoL is a self-administered questionnaire designed to assess health-related quality of life in adult subjects with AS. The ASQoL contains 18 items with a dichotomous yes/no response option. A single point is assigned for each yes response and no points for each no response, resulting in overall scores that range from 0 (least severity) to 18 (highest severity). As such, lower scores indicate better quality of life. Items include an assessment of mobility/energy, self care and mood/emotion. The recall period is at the moment. |
| Percentage of Participants Who Achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Major Improvement | Baseline to Week 16 | ASDAS-CRP was utilized to assess disease activity status. Parameters used for the ASDAS included: total back pain (BASDAI question 2), patient's global assessment of disease activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI question 6) and CRP in mg/L. Disease activity states: inactive disease, moderate disease activity, high disease activity, and very high disease activity. The three values selected to separate these states are: \< 1.3 between inactive disease and moderate disease activity; \< 2.1 between moderate disease activity and high disease activity; and \> 3.5 between high disease activity and very high disease activity. Selected cutoffs for improvement scores are a change of ≥ 1.1 unit for minimal clinically important improvement and a change of ≥ 2.0 units for major improvement . |
| Percentage of Participants Who Achieved an ASAS20 (Assessment of SpondyloArthritis International Society Criteria) | Baseline to Week 16 | The ASAS Response Criteria (ASAS20) is defined as an improvement of ≥20% and ≥1 unit on a scale of 10 in at least three of the four main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain. A higher score on the VAS signifies higher severity. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). |
| The Percentage of Participants Achieving Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Inactive Disease. | Baseline to Week 16 | ASDAS-CRP was utilized to assess disease activity status. Parameters used for the ASDAS included: total back pain (BASDAI question 2), patient's global assessment of disease activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI question 6) and CRP in mg/L. Disease activity states: inactive disease, moderate disease activity, high disease activity, and very high disease activity. The three values selected to separate these states are: \< 1.3 between inactive disease and moderate disease activity; \< 2.1 between moderate disease activity and high disease activity; and \> 3.5 between high disease activity and very high disease activity. Selected cutoffs for improvement scores are a change of ≥ 1.1 unit for minimal clinically important improvement and a change of ≥ 2.0 units for major improvement |
| Percentage of Participants Who Achieved ASAS20 (Assessment of Spondylarthritis International Society Criteria) Partial Remission. | Baseline to Week 16 | ASAS partial remission criteria are defined as a value not above 2 units in each of the four main ASAS domains on a scale of 0-10. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant). |
| Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) | Baseline to Week 16 | The PSQI is a self-report questionnaire that assesses sleep quality over a 1-month time interval. Consisting of 19 items, the PSQI measures several different aspects of sleep, offering seven component scores and one composite score. The component scores consist of subjective sleep quality, sleep latency (i.e., how long it takes to fall asleep), sleep duration, habitual sleep efficiency (i.e., the percentage of time in bed that one is asleep), sleep disturbances, use of sleeping medication, and daytime dysfunction. Each item is weighted on a 0-3 interval scale. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denoted a healthier sleep quality. |
| The Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) | Baseline to Week 16 | This assessment (laboratory assessment) was performed in order to identify the presence of inflammation, to determine its severity and to monitor the response to treatment. Exponentially transformed LSM, the geometric mean ratio of post-baseline/baseline. A value \<1 indicates a reduced CRP |
Countries
Belgium, Brazil, Bulgaria, Colombia, Czechia, Greece, Guatemala, India, Italy, Malaysia, Philippines, Poland, Russia, South Korea, Sweden, Thailand, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
769 participants were screened for the study and 527 participants were randomized. However, one participant was mis-randomized and discontinued prior to dosing and is not included in the table below.
Participants by arm
| Arm | Count |
|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. Participants received AIN457 (secukinumab) 6 mg/kg i.v. at baseline, followed by AIN457 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52) | 264 |
| Placebo - AIN457 3 mg/kg i.v. Participants received i.v. placebo at baseline visit, Weeks 4, 8, and 12, followed by AIN457 (secukinumab) 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52) | 262 |
| Total | 526 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse event - TP 1 | 5 | 2 |
| Overall Study | Adverse event - TP 2 | 5 | 6 |
| Overall Study | Death - TP 2 | 1 | 0 |
| Overall Study | Lost to follow-up TP 1 | 1 | 1 |
| Overall Study | Lost to follow-up - TP 2 | 5 | 2 |
| Overall Study | New therapy for study indication - TP 2 | 1 | 0 |
| Overall Study | Physician decision - TP 2 | 4 | 2 |
| Overall Study | Pregnancy - TP 2 | 1 | 1 |
| Overall Study | Progressive disease - TP 1 | 0 | 1 |
| Overall Study | Subject decision - TP 1 | 3 | 5 |
| Overall Study | Subject decision - TP 2 | 11 | 9 |
Baseline characteristics
| Characteristic | AIN457 6 mg/kg - 3 mg/kg i.v. | Placebo - AIN457 3 mg/kg i.v. | Total |
|---|---|---|---|
| Age, Customized 65 - 75 years | 8 Participants | 4 Participants | 12 Participants |
| Age, Customized < 65 years | 253 Participants | 257 Participants | 510 Participants |
| Age, Customized >= 75 years | 3 Participants | 1 Participants | 4 Participants |
| Disease condition Ankylosing spondylitis | 208 Participants | 205 Participants | 413 Participants |
| Disease condition Non-radiographic axial spondylarthritis | 56 Participants | 57 Participants | 113 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 17 Participants | 25 Participants | 42 Participants |
| Race/Ethnicity, Customized Asian | 59 Participants | 47 Participants | 106 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 180 Participants | 179 Participants | 359 Participants |
| Sex: Female, Male Female | 99 Participants | 84 Participants | 183 Participants |
| Sex: Female, Male Male | 165 Participants | 178 Participants | 343 Participants |
| Weight | 77.61 kg STANDARD_DEVIATION 18.006 | 78.08 kg STANDARD_DEVIATION 18.444 | 77.85 kg STANDARD_DEVIATION 18.21 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 517 | 0 / 261 |
| other Total, other adverse events | 172 / 517 | 35 / 261 |
| serious Total, serious adverse events | 32 / 517 | 3 / 261 |
Outcome results
Primary
Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria)
ASAS40 is ≥ 40% and an absolute improvement from baseline of ≥20 units (range 0-100) in ≥ 3 of the following 4 domains: back pain \[10 cm visual analogue scale (VAS)\], patient global assessment of disease activity (10 cm VAS), physical function (BASFI; range 0-100) and inflammation (mean score of items 5 and 6 of the BASDAI; both 10 cm VAS) without any worsening in the remaining domain. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
Time frame: Baseline to Week 16
Population: Full analysis set with missing responses for any reason imputed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria) | 40.85 percentage of participants |
| Placebo - AIN457 3 mg/kg i.v. | Percentage of Participants Who Achieved an ASAS40 (Assessment of SpondyloArthritis International Society Criteria) | 22.94 percentage of participants |
Comparison: Week 16p-value: <0.000195% CI: [10.12, 25.71]Regression, Logistic
Secondary
Change From Baseline in Pittsburgh Sleep Quality Index (PSQI)
The PSQI is a self-report questionnaire that assesses sleep quality over a 1-month time interval. Consisting of 19 items, the PSQI measures several different aspects of sleep, offering seven component scores and one composite score. The component scores consist of subjective sleep quality, sleep latency (i.e., how long it takes to fall asleep), sleep duration, habitual sleep efficiency (i.e., the percentage of time in bed that one is asleep), sleep disturbances, use of sleeping medication, and daytime dysfunction. Each item is weighted on a 0-3 interval scale. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denoted a healthier sleep quality.
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) | -2.42 scores on a scale | Standard Error 0.222 |
| Placebo - AIN457 3 mg/kg i.v. | Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) | -1.76 scores on a scale | Standard Error 0.221 |
p-value: 0.023495% CI: [-1.24, -0.09]Regression, Logistic
Secondary
Percentage of Participants Who Achieved an ASAS20 (Assessment of SpondyloArthritis International Society Criteria)
The ASAS Response Criteria (ASAS20) is defined as an improvement of ≥20% and ≥1 unit on a scale of 10 in at least three of the four main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain. A higher score on the VAS signifies higher severity. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
Time frame: Baseline to Week 16
Population: Full analysis set with missing responses for any reason imputed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | Percentage of Participants Who Achieved an ASAS20 (Assessment of SpondyloArthritis International Society Criteria) | 63.94 percentage of participants |
| Placebo - AIN457 3 mg/kg i.v. | Percentage of Participants Who Achieved an ASAS20 (Assessment of SpondyloArthritis International Society Criteria) | 40.53 percentage of participants |
p-value: <0.000195% CI: [15.61, 31.66]Regression, Logistic
Secondary
Percentage of Participants Who Achieved an ASAS 5/6 (Assessment of Spondylarthritis International Society Criteria)
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six domains. A higher score on the VAS signifies higher severity. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
Time frame: Baseline to Week 16
Population: Full analysis set with missing responses for any reason imputed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | Percentage of Participants Who Achieved an ASAS 5/6 (Assessment of Spondylarthritis International Society Criteria) | 43.92 Percentage of participaants |
| Placebo - AIN457 3 mg/kg i.v. | Percentage of Participants Who Achieved an ASAS 5/6 (Assessment of Spondylarthritis International Society Criteria) | 21.77 Percentage of participaants |
p-value: <0.000195% CI: [14.36, 29.95]Regression, Logistic
Secondary
Percentage of Participants Who Achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Major Improvement
ASDAS-CRP was utilized to assess disease activity status. Parameters used for the ASDAS included: total back pain (BASDAI question 2), patient's global assessment of disease activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI question 6) and CRP in mg/L. Disease activity states: inactive disease, moderate disease activity, high disease activity, and very high disease activity. The three values selected to separate these states are: \< 1.3 between inactive disease and moderate disease activity; \< 2.1 between moderate disease activity and high disease activity; and \> 3.5 between high disease activity and very high disease activity. Selected cutoffs for improvement scores are a change of ≥ 1.1 unit for minimal clinically important improvement and a change of ≥ 2.0 units for major improvement .
Time frame: Baseline to Week 16
Population: Full analysis set with missing responses for any reason imputed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | Percentage of Participants Who Achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Major Improvement | 27.99 percentage of participants |
| Placebo - AIN457 3 mg/kg i.v. | Percentage of Participants Who Achieved Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Major Improvement | 7.54 percentage of participants |
p-value: <0.000195% CI: [14.45, 26.44]Regression, Logistic
Secondary
Percentage of Participants Who Achieved ASAS20 (Assessment of Spondylarthritis International Society Criteria) Partial Remission.
ASAS partial remission criteria are defined as a value not above 2 units in each of the four main ASAS domains on a scale of 0-10. ASAS consists of 6 domains (4 main and 2 additional): 1. Patient's global assessment measured on a visual analog scale (VAS); 2. Patient's assessment of back pain, measured on a VAS; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) measured by VAS; 4. Inflammation represented by mean duration and severity of morning stiffness, on the BAS Disease Activity Index (BASDAI) as measured by VAS; 5. Spinal mobility represented by the BAS Metrology Index (BASMI) lateral spinal flexion assessment; 6. C-reactive protein (acute phase reactant).
Time frame: Baseline to Week 16
Population: Full analysis set with missing responses for any reason imputed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | Percentage of Participants Who Achieved ASAS20 (Assessment of Spondylarthritis International Society Criteria) Partial Remission. | 14.76 percentage of participants |
| Placebo - AIN457 3 mg/kg i.v. | Percentage of Participants Who Achieved ASAS20 (Assessment of Spondylarthritis International Society Criteria) Partial Remission. | 4.20 percentage of participants |
p-value: <0.000195% CI: [5.64, 15.47]Regression, Logistic
Secondary
The Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQol)
The ASQoL is a self-administered questionnaire designed to assess health-related quality of life in adult subjects with AS. The ASQoL contains 18 items with a dichotomous yes/no response option. A single point is assigned for each yes response and no points for each no response, resulting in overall scores that range from 0 (least severity) to 18 (highest severity). As such, lower scores indicate better quality of life. Items include an assessment of mobility/energy, self care and mood/emotion. The recall period is at the moment.
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | The Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQol) | -4.65 scores on a scale | Standard Error 0.291 |
| Placebo - AIN457 3 mg/kg i.v. | The Change From Baseline in Ankylosing Spondylitis Quality of Life (ASQol) | -2.88 scores on a scale | Standard Error 0.29 |
Comparison: Week 16p-value: <0.000195% CI: [-2.51, -1.04]Mixed Models Analysis
Secondary
The Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP)
This assessment (laboratory assessment) was performed in order to identify the presence of inflammation, to determine its severity and to monitor the response to treatment. Exponentially transformed LSM, the geometric mean ratio of post-baseline/baseline. A value \<1 indicates a reduced CRP
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | The Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) | 0.39 ratio | Standard Error 1.063 |
| Placebo - AIN457 3 mg/kg i.v. | The Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) | 0.89 ratio | Standard Error 1.062 |
Comparison: Week 16p-value: <0.000195% CI: [0.37, 0.51]Mixed Models Analysis
Secondary
The Change From Baseline in Short Form-36 Physical Component Summary (SF-36 PCS)
The Short Form-36 Physical Component Summary (SF-36 PCS) is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of eight subscales (domains) that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role- Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The eight domains are based on a scale from 0-100 while PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. Higher scores indicate a higher level of functioning. A positive change from baseline score indicates an improvement.
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | The Change From Baseline in Short Form-36 Physical Component Summary (SF-36 PCS) | 7.70 scores on a scale | Standard Error 0.473 |
| Placebo - AIN457 3 mg/kg i.v. | The Change From Baseline in Short Form-36 Physical Component Summary (SF-36 PCS) | 4.69 scores on a scale | Standard Error 0.473 |
Comparison: Week 16p-value: <0.000195% CI: [1.8, 4.22]Mixed Models Analysis
Secondary
The Change From Baseline in Total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
BASDAI consists of a 0 through 10 scale (0 indicating no problem and 10 indicating the worst problem, captured as a continuous VAS), which was used to answer six questions pertaining to the five major symptoms of AS: fatigue, spinal pain, peripheral joint pain / swelling,, areas of localized tenderness (enthesitis, or inflammation of tendons and ligaments), morning stiffness duration, morning stiffness severity. To give each symptom equal weight, the mean of the two scores relating to morning stiffness is taken into account (questions 5 and 6). The resulting 0 to 10 score is added to the scores for questions 1 through 4. The resulting 0 to 50 score is divided by 5 to give a final 0 10 BASDAI score.
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | The Change From Baseline in Total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | -2.70 scores on a scale | Standard Error 0.144 |
| Placebo - AIN457 3 mg/kg i.v. | The Change From Baseline in Total Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | -1.69 scores on a scale | Standard Error 0.144 |
Comparison: Week 16p-value: <0.000195% CI: [-1.38, -0.64]Mixed Models Analysis
Secondary
The Change From Baseline in Total Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in subjects with AS. The questions were chosen on the basis of predominant input from subjects with AS. The first eight questions consider activities related to functional anatomy. The final two questions assess the subjects' ability to cope with everyday life. A 0-10 scale (captured as a continuous VAS) is used to answer the questions. The BASFI score is the mean of the ten scales - a value between 0 and 10.
Time frame: Baseline to Week 16
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | The Change From Baseline in Total Bath Ankylosing Spondylitis Functional Index (BASFI) | -2.33 scores on a scale | Standard Error 0.147 |
| Placebo - AIN457 3 mg/kg i.v. | The Change From Baseline in Total Bath Ankylosing Spondylitis Functional Index (BASFI) | -1.39 scores on a scale | Standard Error 0.148 |
Comparison: Week 16p-value: <0.000195% CI: [-1.33, -0.56]Mixed Models Analysis
Secondary
The Percentage of Participants Achieving Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Inactive Disease.
ASDAS-CRP was utilized to assess disease activity status. Parameters used for the ASDAS included: total back pain (BASDAI question 2), patient's global assessment of disease activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI question 6) and CRP in mg/L. Disease activity states: inactive disease, moderate disease activity, high disease activity, and very high disease activity. The three values selected to separate these states are: \< 1.3 between inactive disease and moderate disease activity; \< 2.1 between moderate disease activity and high disease activity; and \> 3.5 between high disease activity and very high disease activity. Selected cutoffs for improvement scores are a change of ≥ 1.1 unit for minimal clinically important improvement and a change of ≥ 2.0 units for major improvement
Time frame: Baseline to Week 16
Population: Full analysis set with missing responses for any reason imputed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 6 mg/kg - 3 mg/kg i.v. | The Percentage of Participants Achieving Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Inactive Disease. | 15.66 percentage of participants |
| Placebo - AIN457 3 mg/kg i.v. | The Percentage of Participants Achieving Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) Inactive Disease. | 3.08 percentage of participants |
Comparison: Week 16p-value: <0.000195% CI: [7.96, 17.19]Regression, Logistic