Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, RA, IL-17 blocker, subcutaneous, self-injection, AIN457, AIN457F, secukinumab, anti-TNFα, pre-filled syringe
Brief summary
This study will provide efficacy and safety data of the secukinumab pre-filled syringe (PFS) for subcutaneous self-administration in patients with active rheumatoid arthritis who are intolerant to or have had an inadequate response to anti-TNF-α agents.
Interventions
BIOLOGICALSecukinumab (AIN457)
Secukinumab is a human monoclonal antibody. Monoclonal antibodies are proteins that recognize and bind to unique proteins that your body produces. Secukinumab binds and reduces the activity of a cytokine (a messenger protein in the body) called Interleukin 17 (IL-17)
BIOLOGICALPlacebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Presence of Rheumatoid Arthritis classified by ACR 2010 revised criteria for at least 3 months •Disease activity defined by ≥6 tender joints out of 68 and ≥ 6 swollen joints out of 66 at baseline and with: Either Anti-CCP antibodies positive OR Rheumatoid Factor positive AND WITH Either hsCRP ≥ 10 mg/L OR ESR ≥28 mm/1st hr •Intake of at least one anti-TNF-α agent such as etanercept, adalimumab, infliximab, certolizumab or golimumab for at least 3 months before entering the study and to have experienced an inadequate response to treatment or to have been intolerant to at least one administration
Exclusion criteria
* Current RA functional status class IV according to the ACR 1991 revised criteria •Previous use of secukinumab or other biologic drug directly targeting IL-17 or IL-17 receptor and/or any history of hypersensitivity to secukinumab or its excipient or to drugs of similar chemical classes. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) | Week 24 | The DAS28 is a measure of disease activity in RA based on Swollen and Tender Joint Counts (out of a total of 28), hsCRP and the Patient's Global Assessment of Disease Activity. A DAS28 score greater than 5.1 implies active disease, equal to or less than 3.2 low disease activity, and less than 2.6 remission. A negative change from baseline indicates improvement. |
| Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | 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. |
| Percentage of Participants Achieving ACR50 | Week 24 | ACR50 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 50% 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 ACR50 response results at week 24 used non-responder imputation. |
Countries
Argentina, Brazil, Colombia, Czechia, Dominican Republic, Germany, Greece, Guatemala, India, Italy, Japan, Panama, Portugal, South Africa, South Korea, United States
Participant flow
Recruitment details
Patients received AIN457 75 mg, AIN457 150 mg or placebo as subcutaneous (s.c.) loading dose once weekly at baseline (BSL), Weeks 1, 2, 3 and 4, followed by monthly maintenance starting at Week 4.
Pre-assignment details
At Wk 16, patients were classified as responders or non-responders. Placebo patients who were non responders were rerandomized at Wk 16 to AIN457 75 mg or AIN457 150 mg (1:1). Patients on placebo who were responders continued to receive placebo until Wk 24, these patients were re-randomized to receive AIN457 75 mg or AIN457 150 mg (1:1).
Participants by arm
| Arm | Count |
|---|---|
| AIN457 75 mg 75 mg secukinumab: Patients on secukinumab 75 mg continued to receive secukinumab 75 mg via PFS every 4 weeks regardless of responder status. | 80 |
| AIN457 150mg 150 mg secukinumab: Patients on secukinumab 150 mg continued to receive secukinumab 150 mg via PFS every 4 weeks regardless of responder status. | 81 |
| Placebo At Wk 16, patients were classified: responders or non-responders. Placebo patients who were non responders were rerandomized at Wk 16 to AIN457 75 mg or AIN457 150 mg (1:1). Patients on placebo who were responders continued to receive placebo until Wk 24, these patients were re-randomized to receive AIN457 75 mg or AIN457 150 mg (1:1) | 81 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 2 |
| Overall Study | Lack of Efficacy | 8 | 6 | 6 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 2 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | study terminated by sponsor | 22 | 23 | 22 |
| Overall Study | Technical issues | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 10 | 7 |
Baseline characteristics
| Characteristic | AIN457 75 mg | AIN457 150mg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 19 Participants | 12 Participants | 41 Participants |
| Age, Categorical Between 18 and 65 years | 70 Participants | 62 Participants | 69 Participants | 201 Participants |
| Sex: Female, Male Female | 70 Participants | 67 Participants | 65 Participants | 202 Participants |
| Sex: Female, Male Male | 10 Participants | 14 Participants | 16 Participants | 40 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 | 77 / 115 | 63 / 115 | 35 / 79 |
| serious Total, serious adverse events | 12 / 115 | 9 / 115 | 0 / 79 |
Outcome results
Primary
Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20).
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: Full analysis set (FAS): The FAS was comprised of all patients from the randomized set to whom study treatment had been assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 75 mg | Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20). | 37.5 percentage of participants |
| AIN457 150mg | Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20). | 38.3 percentage of participants |
| Placebo | Percentage of Participants Achieving an American College of Rheumatology Response 20 (ACR20). | 27.2 percentage of participants |
p-value: 0.200195% CI: [0.79, 3.03]Regression, Logistic
p-value: 0.157495% CI: [0.83, 3.15]Regression, Logistic
Secondary
Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP)
The DAS28 is a measure of disease activity in RA based on Swollen and Tender Joint Counts (out of a total of 28), hsCRP and the Patient's Global Assessment of Disease Activity. A DAS28 score greater than 5.1 implies active disease, equal to or less than 3.2 low disease activity, and less than 2.6 remission. A negative change from baseline indicates improvement.
Time frame: Week 24
Population: Full analysis set (FAS): The FAS was comprised of all patients from the randomized set to whom study treatment had been assigned.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 75 mg | Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) | -1.56 Units on a scale | Standard Error 0.149 |
| AIN457 150mg | Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) | -1.61 Units on a scale | Standard Error 0.148 |
| Placebo | Change From Baseline in Disease Activity Score Utilizing CRP (DAS28-CRP) | -1.01 Units on a scale | Standard Error 0.176 |
Secondary
Change From Baseline 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: Week 24
Population: Full analysis set (FAS): The FAS was comprised of all patients from the randomized set to whom study treatment had been assigned.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AIN457 75 mg | Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | -0.42 units on a scale | Standard Error 0.068 |
| AIN457 150mg | Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | -0.39 units on a scale | Standard Error 0.068 |
| Placebo | Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) | -0.13 units on a scale | Standard Error 0.078 |
Secondary
Percentage of Participants Achieving ACR50
ACR50 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 50% 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 ACR50 response results at week 24 used non-responder imputation.
Time frame: Week 24
Population: Full analysis set: the full analysis set was comprised of all randomized participants (excluding mis-randomized participants) who were assigned to study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AIN457 75 mg | Percentage of Participants Achieving ACR50 | 17.5 Percentage of patients |
| AIN457 150mg | Percentage of Participants Achieving ACR50 | 18.5 Percentage of patients |
| Placebo | Percentage of Participants Achieving ACR50 | 13.6 Percentage of patients |