Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, IgG1K monoclonal antibody, Interleukin-17A neutralizing
Brief summary
This study aims to confirm if patients with a specific biomarker might have a better response to secukinumab treatment. To meet this purpose, exploratory biomarker studies will be done. The goals of these exploratory studies are to (1) find biomarkers that will identify persons with rheumatoid arthritis who will have the best possible response to secukinumab and (2) to identify persons who will have fewer side effects in order to maximize their benefit from secukinumab.
Interventions
DRUGPlacebo
Matching placebo to secukinumab I.V.
DRUGSecukinumab
In part 1 (blinded period), participants randomized to secukinumab received 10 mg/kg I.V.. Participants, enrolled in part 2 (open label), received secukinumab 300 mg subcutaneous.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of rheumatoid arthritis * Patients must be either DMARD naive or have failed at least one DMARD agent (e.g. MTX, leflunamide or sulfasalazine) * Patients are allowed up to 3 DMARDs at study entry (e.g. MTX, sulfasalazine or hydroxychloroquine) as long as their dose was stable for 4 weeks prior to initiating study treatment * Disease activity at screening defined by ≥6 out of 28 tender joints and ≥6 out of 28 swollen joints and hsCRP \>10mg/L
Exclusion criteria
* Patients with severe rheumatoid arthritis (functional status class IV according to the ACR 1991 revised criteria) * Previous exposure to secukinumab or any other biologic, including TNF inhibitors. * Use of high potency opioid analgesics * Pregnant or nursing (lactating) women * Use of any investigational drug other than RA therapy and/or devices at the time of randomization or within 30 days or 5 half-lives of randomization, whichever is longer. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve American College of Rheumatology Response of 20 (ACR20 ) in Association With the Presence or Absence of the HLA-DRB1 *4 Allelic Group | 12 weeks | A participant was considered to be a responder according to the ACR20 criteria if the participant had at least 20% improvement in both the tender joint count and swollen joint count measures, and in at least 3 of the following 5 measures: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ©) score, and/or C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR). |
| Change From Baseline in Disease Activity Score 28 (DAS28) in Association With the Presence or Absence of HLA-DRB1 04 | baseline, 12 weeks | The DAS28 is a measure of disease activity in RA. The score is calculated by a complex mathematical formula, which includes the tender joint count(TJC) and swollen joint count (SJC) out of a total of 28 joints, the high-sensitivity C-reactive protein (hsCRP), and the subject's 'global assessment' of disease activity/general health (GH). The subject's global assessment/GH was indicated by a visual analogue scale of 100 mm where the participant marked a point on a 100 mm line between 0 and 100 (0 indicated very good and 100 indicated very bad). The following formula was used to calculate DAS28: DAS-CRP = 0.56\*sqrt(TJC28) + 0.28\*sqrt(SJC28) = 0.36\*ln(CRP+1) + 0.014\*GH = 0.96. A DAS28-CRP score \> 5.1 implies active disease, \<3.2 implies controlled disease and \<2.6 implied remission. A negative change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | 12 weeks | A participant was considered to be a responder according to the ACR50 or ACR70 criteria if the participant had at least 50% or 70% improvement, respectively, in both the tender joint count and swollen joint count measures, and in at least 3 of the following 5 measures: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ©) score, and/or C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR). |
| Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | baseline, 12 weeks | The DAS28 is a measure of disease activity in RA. The score is calculated by a complex mathematical formula, which includes the tender joint count(TJC) and swollen joint count (SJC) out of a total of 28 joints, the high-sensitivity C-reactive protein (hsCRP), and the subject's 'global assessment' of disease activity/general health (GH). The subject's global assessment/GH was indicated by a visual analogue scale of 100 mm where the participant marked a point on a 100 mm line between 0 and 100 (0 indicated very good and 100 indicated very bad). The following formula was used to calculate DAS28: DAS-CRP = 0.56\*sqrt(TJC28) + 0.28\*sqrt(SJC28) = 0.36\*ln(CRP+1) + 0.014\*GH = 0.96. A DAS28-CRP score \> 5.1 implies active disease, \<3.2 implies controlled disease and \<2.6 implied remission. A negative change from baseline indicates improvement. |
Countries
Belgium, Germany, Russia, United Kingdom, United States
Participant flow
Recruitment details
The study included a 12 week, randomized, double blind phase (part 1), a 40 week, open label phase (part 2), and a 3 month safety follow-up. Participants from the secukinumab arm, who completed part 1 and had an ACR50 or greater response at week 12, and participants from the placebo arm, who completed part 1, were eligible for the open label phase.
Pre-assignment details
One hundred participants received study treatment in part 1. Ten participants discontinued during part 1. At the end of part 1, 76 participants were eligible to take secukinumab treatment in part 2.
Participants by arm
| Arm | Count |
|---|---|
| Secukinumab 10 mg/kg intravenous (I.V.) | 68 |
| Placebo Placebo i.v. | 32 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1 | Adverse Event | 3 | 0 | 0 | 0 | 0 | 0 |
| Part 1 | Lack of Efficacy | 2 | 1 | 0 | 0 | 0 | 0 |
| Part 1 | Lost to Follow-up | 1 | 2 | 0 | 0 | 0 | 0 |
| Part 1 | Protocol deviation | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 2 | Administrative problems | 0 | 0 | 2 | 0 | 1 | 0 |
| Part 2 | Adverse Event | 0 | 0 | 2 | 0 | 1 | 0 |
| Part 2 | Death | 0 | 0 | 1 | 0 | 1 | 0 |
| Part 2 | Lack of Efficacy | 0 | 0 | 5 | 0 | 2 | 0 |
| Part 2 | Lost to Follow-up | 0 | 0 | 4 | 0 | 1 | 0 |
| Part 2 | Protocol deviation | 0 | 0 | 1 | 0 | 0 | 0 |
| Part 2 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Secukinumab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 49.5 Years STANDARD_DEVIATION 11.45 | 54.5 Years STANDARD_DEVIATION 10.3 | 51.1 Years STANDARD_DEVIATION 11.29 |
| Sex: Female, Male Female | 48 Participants | 25 Participants | 73 Participants |
| Sex: Female, Male Male | 20 Participants | 7 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 68 | 9 / 32 | 15 / 49 | 12 / 27 |
| serious Total, serious adverse events | 4 / 68 | 2 / 32 | 4 / 49 | 4 / 27 |
Outcome results
Primary
Change From Baseline in Disease Activity Score 28 (DAS28) in Association With the Presence or Absence of HLA-DRB1 04
The DAS28 is a measure of disease activity in RA. The score is calculated by a complex mathematical formula, which includes the tender joint count(TJC) and swollen joint count (SJC) out of a total of 28 joints, the high-sensitivity C-reactive protein (hsCRP), and the subject's 'global assessment' of disease activity/general health (GH). The subject's global assessment/GH was indicated by a visual analogue scale of 100 mm where the participant marked a point on a 100 mm line between 0 and 100 (0 indicated very good and 100 indicated very bad). The following formula was used to calculate DAS28: DAS-CRP = 0.56\*sqrt(TJC28) + 0.28\*sqrt(SJC28) = 0.36\*ln(CRP+1) + 0.014\*GH = 0.96. A DAS28-CRP score \> 5.1 implies active disease, \<3.2 implies controlled disease and \<2.6 implied remission. A negative change from baseline indicates improvement.
Time frame: baseline, 12 weeks
Population: Participants, who completed part 1, were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Secukinumab | Change From Baseline in Disease Activity Score 28 (DAS28) in Association With the Presence or Absence of HLA-DRB1 04 | HLA-DRB1 *04 carriers | -2.5 score on a scale | Standard Error 0.5273 |
| Secukinumab | Change From Baseline in Disease Activity Score 28 (DAS28) in Association With the Presence or Absence of HLA-DRB1 04 | HLA-DRB1 *04 non-carriers | -2.2 score on a scale | Standard Error 0.5618 |
| Placebo | Change From Baseline in Disease Activity Score 28 (DAS28) in Association With the Presence or Absence of HLA-DRB1 04 | HLA-DRB1 *04 carriers | -0.6 score on a scale | Standard Error 0.575 |
| Placebo | Change From Baseline in Disease Activity Score 28 (DAS28) in Association With the Presence or Absence of HLA-DRB1 04 | HLA-DRB1 *04 non-carriers | -0.8 score on a scale | Standard Error 0.6098 |
Primary
Percentage of Participants Who Achieve American College of Rheumatology Response of 20 (ACR20 ) in Association With the Presence or Absence of the HLA-DRB1 *4 Allelic Group
A participant was considered to be a responder according to the ACR20 criteria if the participant had at least 20% improvement in both the tender joint count and swollen joint count measures, and in at least 3 of the following 5 measures: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ©) score, and/or C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR).
Time frame: 12 weeks
Population: Participants, who completed part 1, were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Secukinumab | Percentage of Participants Who Achieve American College of Rheumatology Response of 20 (ACR20 ) in Association With the Presence or Absence of the HLA-DRB1 *4 Allelic Group | HLADRB1 *04 carriers | 45.2 Percentage of participants |
| Secukinumab | Percentage of Participants Who Achieve American College of Rheumatology Response of 20 (ACR20 ) in Association With the Presence or Absence of the HLA-DRB1 *4 Allelic Group | HLADRB1 *04 non-carriers | 41.9 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve American College of Rheumatology Response of 20 (ACR20 ) in Association With the Presence or Absence of the HLA-DRB1 *4 Allelic Group | HLADRB1 *04 carriers | 10.7 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve American College of Rheumatology Response of 20 (ACR20 ) in Association With the Presence or Absence of the HLA-DRB1 *4 Allelic Group | HLADRB1 *04 non-carriers | 14.3 Percentage of participants |
Secondary
Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers
The DAS28 is a measure of disease activity in RA. The score is calculated by a complex mathematical formula, which includes the tender joint count(TJC) and swollen joint count (SJC) out of a total of 28 joints, the high-sensitivity C-reactive protein (hsCRP), and the subject's 'global assessment' of disease activity/general health (GH). The subject's global assessment/GH was indicated by a visual analogue scale of 100 mm where the participant marked a point on a 100 mm line between 0 and 100 (0 indicated very good and 100 indicated very bad). The following formula was used to calculate DAS28: DAS-CRP = 0.56\*sqrt(TJC28) + 0.28\*sqrt(SJC28) = 0.36\*ln(CRP+1) + 0.014\*GH = 0.96. A DAS28-CRP score \> 5.1 implies active disease, \<3.2 implies controlled disease and \<2.6 implied remission. A negative change from baseline indicates improvement.
Time frame: baseline, 12 weeks
Population: Participants, who completed part 1, were included in the analysis. Statistical analysis was not done on the other biomarkers: osteoprotegerin (OPG), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (CCP) and hsCRP. Therefore, data is provided for the alleles only.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Secukinumab | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *SE carrier | -2.6 score on a scale | Standard Error 0.5049 |
| Secukinumab | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *SE non-carrier | -2.3 score on a scale | Standard Error 0.5376 |
| Secukinumab | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *0401 carrier | -2.4 score on a scale | Standard Error 0.5922 |
| Secukinumab | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *401 non-carrier | -2.3 score on a scale | Standard Error 0.5133 |
| Secukinumab | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 position 11 V/L carrier | -2.5 score on a scale | Standard Error 0.4901 |
| Secukinumab | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 position 11 V/L non-carrier | -2.2 score on a scale | Standard Error 0.5706 |
| Placebo | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 position 11 V/L carrier | -0.4 score on a scale | Standard Error 0.5218 |
| Placebo | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *SE carrier | -0.5 score on a scale | Standard Error 5240 |
| Placebo | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *401 non-carrier | -0.9 score on a scale | Standard Error 0.5456 |
| Placebo | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *SE non-carrier | -2.2 score on a scale | Standard Error 0.6977 |
| Placebo | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 position 11 V/L non-carrier | -2.2 score on a scale | Standard Error 0.6954 |
| Placebo | Change From Baseline in DAS28 in Association With the Presence or Absence of HLA-DRB1 *SE (Positive), HLA-DRB1 *401 (Carrier) and HLA-DRB1 Position 11 V/L and in Association With Other Biomarkers | HLA-DRB1 *0401 carrier | 0.1 score on a scale | Standard Error 0.7503 |
Secondary
Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group
A participant was considered to be a responder according to the ACR50 or ACR70 criteria if the participant had at least 50% or 70% improvement, respectively, in both the tender joint count and swollen joint count measures, and in at least 3 of the following 5 measures: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, Health Assessment Questionnaire (HAQ©) score, and/or C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR).
Time frame: 12 weeks
Population: Participants, who completed part 1, were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Secukinumab | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR50: HLADRB1 *04 presence | 38.7 Percentage of participants |
| Secukinumab | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR50: HLADRB1 *04 absence | 35.5 Percentage of participants |
| Secukinumab | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR70: HLADRB1 *04 presence | 8.1 Percentage of participants |
| Secukinumab | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR70: HLADRB1 *04 absence | 8.1 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR70: HLADRB1 *04 absence | 7.1 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR50: HLADRB1 *04 presence | 7.1 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR70: HLADRB1 *04 presence | 0.0 Percentage of participants |
| Placebo | Percentage of Participants Who Achieve ACR50 and ACR70 With the Presence/Absence of the HLA-DRB1*04 Allelic Group | ACR50: HLADRB1 *04 absence | 10.7 Percentage of participants |