Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, RA, ACR, inflammatory joints
Brief summary
The core and extension studies assessed the safety and efficacy of secukinumab when added to a background therapy in patients with active rheumatoid arthritis who are intolerant to or have had an inadequate response to anti-TNF-α agents. Patients received either secukinumab, placebo. The core study was completed. However, the extension study was terminated early (unrelated to safety) due to the results of study AIN457F2309, which indicated the efficacy of AIN457 was not comparable to the currently available RA treatment, abatacept, thus leading to closing of the AIN457 RA program.
Detailed description
CAIN457F2302 (Core Study): Completed Sep 9 2015 CAIN457F2302E1 (Extension study): terminated early May 26 2015, ((unrelated to safety) due to the results of study AIN457F2309, which indicated the efficacy of AIN457 was not comparable to the currently available RA treatment, abatacept, thus leading to closing of the AIN457 RA program.
Interventions
BIOLOGICALSecukinumab (AIN457)
AIN457 (Secukinumab) is a human monoclonal antibody. Secukinumab binds and reduces the activity of Interleukin 17 (IL- 17). AIN457 was given as i.v. (10mg/kg) at baseline, week 2 and week 4, and then s.c. (75 or 150mg) every 4 weeks starting at week 8.
BIOLOGICALPlacebo
Placebo was given as i.v. at baseline, week 2 and week 4, and then s.c. every 4 weeks starting at week 8.
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 * Presence of RA classified by American College of Rheumatology (ACR) 2010 revised criteria for at least 3 months before screening * At Baseline: Disease activity criteria defined by ≥ 6 tender joints out of 68 and ≥6 swollen joints out of 66 with at least 1 of the following at screening: * Anti-Cyclic Citrullinated Peptide (CCP) antibodies positive OR Rheumatoid Factor positive and with at least 1 of the following at screening: * High sensitivity C-reactive protein (hsCRP) ≥ 10 mg/L OR Erythrocyte sedimentation rate (ESR) ≥ 28 mm/1st hr * Patients must have been taking at least one anti-TNF-α agent given at an approved dose for at least 3 months before randomization and have experienced an inadequate response to treatment or have been intolerant to at least one administration of an anti-TNF-α agent * Patients must be taking MTX for at least 3 months before randomization and have to be on a stable dose at least 4 weeks before randomization (7.5 to 25 mg/week For Japan only: 6 to 25 mg/week)
Exclusion criteria
* Chest x-ray with evidence of ongoing infectious or malignant process, obtained within 3 months prior to screening and evaluated by a qualified physician RA patients functional status class IV according to the ACR 1991 revised criteria * Patients who have ever received biologic immunomodulating agents except for those targeting TNFα * Previous treatment with any cell-depleting therapies including but not limited to anti-CD20, investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19) * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Core Study: Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20) at Week 24 | Week 24 | ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR20 response results at week 24 used non-responder imputation. |
| Extension Phase: Percentage of Patients Achieving a American College of Rheumatology Response ACR20, ACR50 and ACR70 | up to week 260 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Core Study Percentage of Patients Achieving Major Clinical Response (Continuous Six-month Period of ACR70 Response During the 1 Year Period) at Week 52 | 52 week | The major clinical response is defined as continuous six-month period of ACR70 response during the 1 year period. ACR70 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 70% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR70 response results at week 24 used non-responder imputation. |
| Extension Phase: Change in Baseline of RA Disease Activity as Measured by Disease Activity Score (DAS28) | week 260 | The DAS28 score is a measure of RA disease activity calculated using variables such as swollen joint count, the Erythrocyte Sedimentation Rate (ESR) and patient reported assessment of health. Using this data, the DAS28 calculation provides a number on a scale from 0-10 indicating the current activity of a patient's RA. A DAS28 score above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 score lower than 2.6. |
| Extension Phase: Proportion of Subjects Achieving Low Disease Activity and Good/Moderate European League Against Rheumatism (EULAR) Responses | up to week 260 | Low Disease Activity is defined as DAS28 ≤ 3.2. EULAR good response requires an improvement of \> 1.2 in the DAS28 score with a present score of ≤3.2; EULAR moderate response is defined as an improvement of \>0.6 to ≤1.2 in DAS28 and a present score of ≤5.1; or an improvement of \>1.2 and a present score of \>3.2. |
| Core Study: Change From Baseline and Week 24 in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | Baseline, Week 24 | The HAQ-DI assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, are you able to... perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement. |
| Extension Phase: Changes in Baseline of Quality of Life (Qol) Outcomes Measured by Medical Outcome Short Form SF-36 v2 | Baseline, up to week 260 | Short Form Health Survey (SF-36) consists of eight subscales 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. |
| Extension Phase: Immunogenicity Against Secukinumab | up to week 260 | — |
| Extension Phase: Proportion of Subjects Achieving ACR/(EULAR) Remission | up to week 260 | ACR/EULAR remission is defined as SDAI ≤ 3.3, where SDAI is a measure of disease activity in RA based on 28 tender and swollen joint counts, CRP, Physician and Patient's Global Assessments of Disease |
| Core Study: Change From Baseline at Week 24 in Van Der Heijde Total Modified Sharp Score | Week 24 | Separate radiographs of each hand/wrist and each foot were taken at basline and Week 24. The radiographs were assessed using the van der Heijde modified Sharp score. The change in the Van der Heijde modified Sharp score is calculated against the baseline value. The total van der Heide modified Sharp score goes from 0 to 448, the bigger the change, the worse it is for the patient. |
Countries
Argentina, Belgium, Canada, Colombia, Guatemala, Hungary, India, Italy, Japan, Mexico, Panama, Puerto Rico, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
At baseline, participants were randomized to 1 of 3 treatment groups. Placebo non- responders at week 16 were re-randomized to receive AIN457 75mg or AIN457 150mg. Placebo responders at Week16 were re-randomized to receive AIN457 75mg or AIN457 150mg at Week 24.
Participants by arm
| Arm | Count |
|---|---|
| AIN457 10mg/Kg-75mg Participants received AIN457 i.v. (10 mg/kg) at Baseline (BSL), Weeks 2 and 4 then AIN457 75 mg s.c. at Week 8 and injected every 4 weeks | 210 |
| AIN457 10mg/Kg-150mg Participants received AIN457 i.v. (10 mg/kg) at BSL, Weeks 2 and 4 then AIN457 150 mg s.c. at Week 8 and injected every 4 weeks | 213 |
| Placebo Participants received matching placebo to AIN457 until week 16 or week 24 based on responder status (\>= 20% reduction in tender and swollen joint count). Non-responders were switched to active treatment at week 16. Responders were switched to active treatment at week 24 | 214 |
| Total | 637 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Study | Adverse Event | 10 | 14 | 13 |
| Core Study | Death | 1 | 1 | 1 |
| Core Study | Lack of Efficacy | 41 | 28 | 37 |
| Core Study | Lost to Follow-up | 7 | 5 | 4 |
| Core Study | No Longer require treatment | 0 | 0 | 1 |
| Core Study | Non-Compliant with study treatment | 0 | 0 | 1 |
| Core Study | Physician Decision | 5 | 4 | 10 |
| Core Study | Pregnancy | 0 | 0 | 1 |
| Core Study | Protocol Violation | 7 | 3 | 2 |
| Core Study | Study terminated by Sponsor | 47 | 54 | 46 |
| Core Study | Technical problems | 1 | 0 | 0 |
| Core Study | Withdrawal by Subject | 15 | 23 | 18 |
| Extension Study, Weeks 104-260 | Adverse Event | 0 | 2 | 1 |
| Extension Study, Weeks 104-260 | Lack of Efficacy | 3 | 0 | 0 |
| Extension Study, Weeks 104-260 | Lost to Follow-up | 0 | 0 | 1 |
| Extension Study, Weeks 104-260 | Physician Decision | 1 | 0 | 0 |
| Extension Study, Weeks 104-260 | Study terminated by sponsor | 52 | 69 | 63 |
| Extension Study, Weeks 104-260 | Withdrawal by Subject | 1 | 0 | 3 |
Baseline characteristics
| Characteristic | Total | AIN457 10mg/Kg-75mg | AIN457 10mg/Kg-150mg | Placebo |
|---|---|---|---|---|
| Age, Customized <65 years | 535 Particpants | 177 Particpants | 176 Particpants | 182 Particpants |
| Age, Customized >=65 years | 102 Particpants | 33 Particpants | 37 Particpants | 32 Particpants |
| Sex: Female, Male Female | 556 Participants | 186 Participants | 188 Participants | 182 Participants |
| Sex: Female, Male Male | 81 Participants | 24 Participants | 25 Participants | 32 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 | 184 / 301 | 225 / 392 | 91 / 214 |
| serious Total, serious adverse events | 33 / 301 | 48 / 392 | 9 / 214 |
Outcome results
Primary
Core Study: Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20) at Week 24
ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR20 response results at week 24 used non-responder imputation.
Time frame: Week 24
Population: The Full analysis set (FAS) comprised all patients who were randomized and to whom study treatment had been assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 10mg/Kg-75mg | Core Study: Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20) at Week 24 | 35.2 Percentage of Participants |
| AIN457 10mg/Kg-150mg | Core Study: Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20) at Week 24 | 35.2 Percentage of Participants |
| Placebo | Core Study: Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20) at Week 24 | 19.6 Percentage of Participants |
p-value: 0.000495% CI: [1.4, 3.4]Regression, Logistic
p-value: 0.000495% CI: [1.4, 3.4]Regression, Logistic
Primary
Extension Phase: Percentage of Patients Achieving a American College of Rheumatology Response ACR20, ACR50 and ACR70
Time frame: up to week 260
Population: The outcome measures were not analyzed, as a result of the lack of efficacy found in study AIN457F2309 and as per changes to the planned analysis plan for CAIN457f2302/E1
Secondary
Core Study: Change From Baseline and Week 24 in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI)
The HAQ-DI assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, are you able to... perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement.
Time frame: Baseline, Week 24
Population: Participants from the full analysis set were considered for the analysis. Participants with measurements at both baseline and week 24 were analyzed. The full analysis set was comprised of all randomized participants (excluding mis-randomized participants) who were assigned to study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 10mg/Kg-75mg | Core Study: Change From Baseline and Week 24 in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | -0.35 Score on a scale | Standard Error 0.039 |
| AIN457 10mg/Kg-150mg | Core Study: Change From Baseline and Week 24 in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | -0.35 Score on a scale | Standard Error 0.038 |
| Placebo | Core Study: Change From Baseline and Week 24 in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | -0.24 Score on a scale | Standard Error 0.051 |
Secondary
Core Study: Change From Baseline at Week 24 in Van Der Heijde Total Modified Sharp Score
Separate radiographs of each hand/wrist and each foot were taken at basline and Week 24. The radiographs were assessed using the van der Heijde modified Sharp score. The change in the Van der Heijde modified Sharp score is calculated against the baseline value. The total van der Heide modified Sharp score goes from 0 to 448, the bigger the change, the worse it is for the patient.
Time frame: Week 24
Population: Participants from the full analysis set were considered for the analysis. Participants with measurements at both baseline and week 24 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AIN457 10mg/Kg-75mg | Core Study: Change From Baseline at Week 24 in Van Der Heijde Total Modified Sharp Score | 0.59 Score on a scale | Standard Error 0.62 |
| AIN457 10mg/Kg-150mg | Core Study: Change From Baseline at Week 24 in Van Der Heijde Total Modified Sharp Score | 0.83 Score on a scale | Standard Error 0.68 |
| Placebo | Core Study: Change From Baseline at Week 24 in Van Der Heijde Total Modified Sharp Score | 1.73 Score on a scale | Standard Error 0 |
Secondary
Core Study Percentage of Patients Achieving Major Clinical Response (Continuous Six-month Period of ACR70 Response During the 1 Year Period) at Week 52
The major clinical response is defined as continuous six-month period of ACR70 response during the 1 year period. ACR70 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 70% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR70 response results at week 24 used non-responder imputation.
Time frame: 52 week
Population: The Full analysis set (FAS) comprised all patients who were randomized and to whom study treatment had been assigned. N=The total number of subjects in the treatment groups with evaluation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 10mg/Kg-75mg | Core Study Percentage of Patients Achieving Major Clinical Response (Continuous Six-month Period of ACR70 Response During the 1 Year Period) at Week 52 | 2.4 Percentage of Participants |
| AIN457 10mg/Kg-150mg | Core Study Percentage of Patients Achieving Major Clinical Response (Continuous Six-month Period of ACR70 Response During the 1 Year Period) at Week 52 | 0.9 Percentage of Participants |
| Placebo | Core Study Percentage of Patients Achieving Major Clinical Response (Continuous Six-month Period of ACR70 Response During the 1 Year Period) at Week 52 | 1.4 Percentage of Participants |
Secondary
Extension Phase: Change in Baseline of RA Disease Activity as Measured by Disease Activity Score (DAS28)
The DAS28 score is a measure of RA disease activity calculated using variables such as swollen joint count, the Erythrocyte Sedimentation Rate (ESR) and patient reported assessment of health. Using this data, the DAS28 calculation provides a number on a scale from 0-10 indicating the current activity of a patient's RA. A DAS28 score above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 score lower than 2.6.
Time frame: week 260
Population: The outcome measures were not analyzed, as a result of the lack of efficacy found in study AIN457F2309 and as per changes to the planned analysis plan for CAIN457f2302/E1
Secondary
Extension Phase: Changes in Baseline of Quality of Life (Qol) Outcomes Measured by Medical Outcome Short Form SF-36 v2
Short Form Health Survey (SF-36) consists of eight subscales 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.
Time frame: Baseline, up to week 260
Population: The outcome measures were not analyzed, as a result of the lack of efficacy found in study AIN457F2309 and as per changes to the planned analysis plan for CAIN457f2302/E1
Secondary
Extension Phase: Immunogenicity Against Secukinumab
Time frame: up to week 260
Population: The outcome measures were not analyzed, as a result of the lack of efficacy found in study AIN457F2309 and as per changes to the planned analysis plan for CAIN457f2302/E1
Secondary
Extension Phase: Proportion of Subjects Achieving ACR/(EULAR) Remission
ACR/EULAR remission is defined as SDAI ≤ 3.3, where SDAI is a measure of disease activity in RA based on 28 tender and swollen joint counts, CRP, Physician and Patient's Global Assessments of Disease
Time frame: up to week 260
Population: The outcome measures were not analyzed, as a result of the lack of efficacy found in study AIN457F2309 and as per changes to the planned analysis plan for CAIN457f2302/E1
Secondary
Extension Phase: Proportion of Subjects Achieving Low Disease Activity and Good/Moderate European League Against Rheumatism (EULAR) Responses
Low Disease Activity is defined as DAS28 ≤ 3.2. EULAR good response requires an improvement of \> 1.2 in the DAS28 score with a present score of ≤3.2; EULAR moderate response is defined as an improvement of \>0.6 to ≤1.2 in DAS28 and a present score of ≤5.1; or an improvement of \>1.2 and a present score of \>3.2.
Time frame: up to week 260
Population: The outcome measures were not analyzed, as a result of the lack of efficacy found in study AIN457F2309 and as per changes to the planned analysis plan for CAIN457f2302/E1