Enthesitis Related Arthritis (ERA)
Conditions
Keywords
inflammatory back pain, ankylosing spondylitis, sacroiliitis, Juvenile Idiopathic Arthritis, enthesitis, arthritis
Brief summary
The purpose of this study is to evaluate the efficacy and safety of adalimumab given subcutaneously every other week (eow) as compared to placebo in pediatric subjects with Enthesitis Related Arthritis (ERA).
Interventions
BIOLOGICALadalimumab
Adalimumab solution for subcutaneous injection.
BIOLOGICALplacebo for adalimumab
Placebo for adalimumab solution for subcutaneous injection.
Sponsors
AbbVie (prior sponsor, Abbott)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Enthesitis Related Arthritis (ERA) as defined by International League of Associations for Rheumatology (ILAR); * Disease activity defined as at least 3 active joints and evidence of enthesitis in at least one location; * Inadequate response or intolerance to at least one nonsteroidal anti-inflammatory drug and at least one disease modifying anti-rheumatic drug, either sulfasalazine or methotrexate.
Exclusion criteria
* Any ILAR Juvenile Idiopathic Arthritis (JIA) subtype other than ERA; * Psoriasis or a history of psoriasis in the patient or first-degree relative; * Presence of Immunoglobulin M (IgM) rheumatoid factor; * Presence of systemic JIA; * History of inflammatory bowel disease; * previous biologic therapy including anti-tumor necrosis factor (anti-TNF) therapy with a potential impact on pediatric ERA; * Infection(s) requiring treatment with IV anti-infectives within 30 days prior to Baseline or oral anti-infectives within 14 days prior to Baseline.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Number of Active Joints With Arthritis From Baseline to Week 12 | Baseline and Week 12 | A joint assessment was recorded at all study visits to assess the number of active joints. A total of 72 joints were assessed for swelling not due to deformity or joints with loss of motion (LOM) plus pain and/or tenderness. Total possible scores ranges from 0 (no active joints) to 72 (all active joints). Baseline is defined as the last nonmissing value prior to the first dose of study drug. Last Observation Carried Forward (LOCF) was used for missing data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tender Joint Count (TJC72): Change From Baseline to Week 12 | Baseline and Week 12 | Seventy-two joints were assessed by pressure on physical examination. Joint tenderness was classified as either present or absent. Scores range from 0 to 72, with higher scores representing higher disease activity. Baseline is defined as the last nonmissing value prior to the first dose of study drug. LOCF was used. |
| Swollen Joint Count (SJC68): Change From Baseline to Week 12 | Baseline and Week 12 | Sixty-eight joints were assessed by physical examination. Joint swelling was classified as present or absent. Scores range from 0 to 68, with higher scores representing higher disease activity. Baseline is defined as the last nonmissing value prior to the first dose of study drug. LOCF was used. |
| Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 30% Response (ACR Pedi30) | Baseline and Week 12 | The ACR Pedi30 response is defined as ≥30% improvement in at least 3 of 6 juvenile rheumatoid arthritis (JRA) core set criteria with no more than 1 of the 6 criteria with \>30% worsening. The 6 variables for the JRA core set criteria are Physician's Global Assessment (PGA) of participant's disease activity, Parent's Global Assessment of participant's overall well-being, number of active joints (joints with swelling not due to deformity or joints LOM plus pain and/or tenderness), number of joints with LOM, Childhood Health Assessment Questionnaire (CHAQ), and high sensitivity C-reactive protein (hs CRP). Baseline is the last value prior to the first dose of study drug. Non-responder imputation (NRI) was used for missing data. |
| Number of Sites of Enthesitis: Change From Baseline to Week 12 | Baseline and Week 12 | The presence of enthesitis was assessed by pressure at 35 anatomical locations. Enthesitis was classifed as either present or absent. Scores range from 0 to 35, with higher scores representing higher disease activity. Baseline is defined as the last nonmissing value prior to the first dose of study drug. LOCF was used. |
| Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 70% Response (ACR Pedi70) | Baseline and Week 12 | The ACR Pedi70 response is defined as ≥70% improvement in at least 3 of 6 JRA core set criteria with no more than 1 of the 6 criteria with \>30% worsening. The 6 variables for the JRA core set criteria are Physician's Global Assessment (PGA) of participant's disease activity, Parent's Global Assessment of participant's overall well-being, number of active joints (joints with swelling not due to deformity or joints LOM plus pain and/or tenderness), number of joints with LOM, Childhood Health Assessment Questionnaire (CHAQ), and high sensitivity C-reactive protein (hs CRP). Baseline is the last value prior to the first dose of study drug. Non-responder imputation NRI was used. |
| Number of Participants With Adverse Events (AEs) | Treatment-emergent AEs (TEAEs) were collected from first dose of study drug until 70 days after the last dose of study drug (up to 212 weeks) | An AE is any untoward medical occurrence in a participant which does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs or TESAE) are defined as any event that began or worsened in severity after the first dose of study drug. The investigator assessed the relationship of each event to the use of study drug as either probably related to study drug, possibly related to study drug, probably not related, or not related to study drug. For more details on adverse events please see the AE section below. |
| Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 50% Response (ACR Pedi50) | Baseline and Week 12 | The ACR Pedi50 response is defined as ≥50% improvement in at least 3 of 6 JRA core set criteria with no more than 1 of the 6 criteria with \>30% worsening. The 6 variables for the JRA core set criteria are Physician's Global Assessment (PGA) of participant's disease activity, Parent's Global Assessment of participant's overall well-being, number of active joints (joints with swelling not due to deformity or joints LOM plus pain and/or tenderness), number of joints with LOM, Childhood Health Assessment Questionnaire (CHAQ), and high sensitivity C-reactive protein (hs CRP). Baseline is the last value prior to the first dose of study drug. NRI was used. |
Participant flow
Recruitment details
The study included a 30-day screening period.
Participants by arm
| Arm | Count |
|---|---|
| Double-blind Placebo EOW Placebo for adalimumab every other week (eow) for 12 weeks. | 15 |
| Double-blind Adalimumab EOW Adalimumab (body surface area dosing 24 mg/m\^2 up to a maximum of 40 mg) every other week (eow) for 12 weeks. | 31 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Period | Adverse Event | 0 | 0 | 6 |
| Open-label Period | Irregular Compliance | 0 | 0 | 1 |
| Open-label Period | Lack of Efficacy | 0 | 0 | 2 |
| Open-label Period | Remission | 0 | 0 | 4 |
| Open-label Period | Withdrawal by Subject | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Double-blind Placebo EOW | Double-blind Adalimumab EOW | Total |
|---|---|---|---|
| Age, Continuous | 11.9 years STANDARD_DEVIATION 2.85 | 13.4 years STANDARD_DEVIATION 2.86 | 12.9 years STANDARD_DEVIATION 2.92 |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 9 Participants | 22 Participants | 31 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 | 8 / 15 | 21 / 31 | 46 / 46 |
| serious Total, serious adverse events | 0 / 15 | 1 / 31 | 10 / 46 |
Outcome results
Primary
Percent Change in Number of Active Joints With Arthritis From Baseline to Week 12
A joint assessment was recorded at all study visits to assess the number of active joints. A total of 72 joints were assessed for swelling not due to deformity or joints with loss of motion (LOM) plus pain and/or tenderness. Total possible scores ranges from 0 (no active joints) to 72 (all active joints). Baseline is defined as the last nonmissing value prior to the first dose of study drug. Last Observation Carried Forward (LOCF) was used for missing data.
Time frame: Baseline and Week 12
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Placebo EOW | Percent Change in Number of Active Joints With Arthritis From Baseline to Week 12 | -11.6 percent change | Standard Deviation 100.5 |
| Double-blind Adalimumab EOW | Percent Change in Number of Active Joints With Arthritis From Baseline to Week 12 | -62.6 percent change | Standard Deviation 59.53 |
p-value: =0.03995% CI: [-99.69, -2.66]ANCOVA
Secondary
Number of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant which does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs or TESAE) are defined as any event that began or worsened in severity after the first dose of study drug. The investigator assessed the relationship of each event to the use of study drug as either probably related to study drug, possibly related to study drug, probably not related, or not related to study drug. For more details on adverse events please see the AE section below.
Time frame: Treatment-emergent AEs (TEAEs) were collected from first dose of study drug until 70 days after the last dose of study drug (up to 212 weeks)
Population: Safety population: All randomized subjects who received at least 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Double-blind Placebo EOW | Number of Participants With Adverse Events (AEs) | Any TEAE | 8 participants |
| Double-blind Placebo EOW | Number of Participants With Adverse Events (AEs) | TEAEs at least possibly related to study drug | 4 participants |
| Double-blind Placebo EOW | Number of Participants With Adverse Events (AEs) | Any severe TEAE | 0 participants |
| Double-blind Placebo EOW | Number of Participants With Adverse Events (AEs) | TESAE | 0 participants |
| Double-blind Placebo EOW | Number of Participants With Adverse Events (AEs) | Any TEAE Leading to Discontinuation of Study | 0 participants |
| Double-blind Placebo EOW | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Double-blind Adalimumab EOW | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Double-blind Adalimumab EOW | Number of Participants With Adverse Events (AEs) | Any TEAE | 21 participants |
| Double-blind Adalimumab EOW | Number of Participants With Adverse Events (AEs) | TESAE | 1 participants |
| Double-blind Adalimumab EOW | Number of Participants With Adverse Events (AEs) | Any TEAE Leading to Discontinuation of Study | 0 participants |
| Double-blind Adalimumab EOW | Number of Participants With Adverse Events (AEs) | TEAEs at least possibly related to study drug | 9 participants |
| Double-blind Adalimumab EOW | Number of Participants With Adverse Events (AEs) | Any severe TEAE | 0 participants |
| Any Adalimumab | Number of Participants With Adverse Events (AEs) | TEAEs at least possibly related to study drug | 29 participants |
| Any Adalimumab | Number of Participants With Adverse Events (AEs) | Any severe TEAE | 7 participants |
| Any Adalimumab | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Any Adalimumab | Number of Participants With Adverse Events (AEs) | TESAE | 10 participants |
| Any Adalimumab | Number of Participants With Adverse Events (AEs) | Any TEAE | 46 participants |
| Any Adalimumab | Number of Participants With Adverse Events (AEs) | Any TEAE Leading to Discontinuation of Study | 7 participants |
Secondary
Number of Sites of Enthesitis: Change From Baseline to Week 12
The presence of enthesitis was assessed by pressure at 35 anatomical locations. Enthesitis was classifed as either present or absent. Scores range from 0 to 35, with higher scores representing higher disease activity. Baseline is defined as the last nonmissing value prior to the first dose of study drug. LOCF was used.
Time frame: Baseline and Week 12
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo EOW | Number of Sites of Enthesitis: Change From Baseline to Week 12 | Baseline | 7.8 sites of enthesitis | Standard Deviation 7.49 |
| Double-blind Placebo EOW | Number of Sites of Enthesitis: Change From Baseline to Week 12 | Week 12 | 5.1 sites of enthesitis | Standard Deviation 8.92 |
| Double-blind Placebo EOW | Number of Sites of Enthesitis: Change From Baseline to Week 12 | Change from Baseline to Week 12 | -2.7 sites of enthesitis | Standard Deviation 4.98 |
| Double-blind Adalimumab EOW | Number of Sites of Enthesitis: Change From Baseline to Week 12 | Baseline | 8.3 sites of enthesitis | Standard Deviation 8.89 |
| Double-blind Adalimumab EOW | Number of Sites of Enthesitis: Change From Baseline to Week 12 | Week 12 | 3.9 sites of enthesitis | Standard Deviation 6.6 |
| Double-blind Adalimumab EOW | Number of Sites of Enthesitis: Change From Baseline to Week 12 | Change from Baseline to Week 12 | -4.4 sites of enthesitis | Standard Deviation 6.2 |
p-value: =0.38295% CI: [-5.32, 2.08]1-way ANOVA
Secondary
Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 30% Response (ACR Pedi30)
The ACR Pedi30 response is defined as ≥30% improvement in at least 3 of 6 juvenile rheumatoid arthritis (JRA) core set criteria with no more than 1 of the 6 criteria with \>30% worsening. The 6 variables for the JRA core set criteria are Physician's Global Assessment (PGA) of participant's disease activity, Parent's Global Assessment of participant's overall well-being, number of active joints (joints with swelling not due to deformity or joints LOM plus pain and/or tenderness), number of joints with LOM, Childhood Health Assessment Questionnaire (CHAQ), and high sensitivity C-reactive protein (hs CRP). Baseline is the last value prior to the first dose of study drug. Non-responder imputation (NRI) was used for missing data.
Time frame: Baseline and Week 12
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo EOW | Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 30% Response (ACR Pedi30) | 60.0 percentage of participants |
| Double-blind Adalimumab EOW | Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 30% Response (ACR Pedi30) | 71.0 percentage of participants |
p-value: =0.51495% CI: [-18.5, 40.5]Fisher Exact
Secondary
Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 50% Response (ACR Pedi50)
The ACR Pedi50 response is defined as ≥50% improvement in at least 3 of 6 JRA core set criteria with no more than 1 of the 6 criteria with \>30% worsening. The 6 variables for the JRA core set criteria are Physician's Global Assessment (PGA) of participant's disease activity, Parent's Global Assessment of participant's overall well-being, number of active joints (joints with swelling not due to deformity or joints LOM plus pain and/or tenderness), number of joints with LOM, Childhood Health Assessment Questionnaire (CHAQ), and high sensitivity C-reactive protein (hs CRP). Baseline is the last value prior to the first dose of study drug. NRI was used.
Time frame: Baseline and Week 12
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo EOW | Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 50% Response (ACR Pedi50) | 40.0 percentage of participants |
| Double-blind Adalimumab EOW | Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 50% Response (ACR Pedi50) | 67.7 percentage of participants |
p-value: =0.11195% CI: [-2, 57.5]Fisher Exact
Secondary
Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 70% Response (ACR Pedi70)
The ACR Pedi70 response is defined as ≥70% improvement in at least 3 of 6 JRA core set criteria with no more than 1 of the 6 criteria with \>30% worsening. The 6 variables for the JRA core set criteria are Physician's Global Assessment (PGA) of participant's disease activity, Parent's Global Assessment of participant's overall well-being, number of active joints (joints with swelling not due to deformity or joints LOM plus pain and/or tenderness), number of joints with LOM, Childhood Health Assessment Questionnaire (CHAQ), and high sensitivity C-reactive protein (hs CRP). Baseline is the last value prior to the first dose of study drug. Non-responder imputation NRI was used.
Time frame: Baseline and Week 12
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo EOW | Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 70% Response (ACR Pedi70) | 20.0 percentage of participants |
| Double-blind Adalimumab EOW | Percentage of Participants Achieving Pediatric American College of Rheumatology Pediatric 70% Response (ACR Pedi70) | 54.8 percentage of participants |
p-value: =0.03195% CI: [8.1, 61.6]Fisher Exact
Secondary
Swollen Joint Count (SJC68): Change From Baseline to Week 12
Sixty-eight joints were assessed by physical examination. Joint swelling was classified as present or absent. Scores range from 0 to 68, with higher scores representing higher disease activity. Baseline is defined as the last nonmissing value prior to the first dose of study drug. LOCF was used.
Time frame: Baseline and Week 12
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo EOW | Swollen Joint Count (SJC68): Change From Baseline to Week 12 | Baseline | 5.2 units on a scale | Standard Deviation 3.69 |
| Double-blind Placebo EOW | Swollen Joint Count (SJC68): Change From Baseline to Week 12 | Week 12 | 2.8 units on a scale | Standard Deviation 2.83 |
| Double-blind Placebo EOW | Swollen Joint Count (SJC68): Change From Baseline to Week 12 | Change from Baseline to Week 12 | -2.4 units on a scale | Standard Deviation 4.66 |
| Double-blind Adalimumab EOW | Swollen Joint Count (SJC68): Change From Baseline to Week 12 | Baseline | 6.7 units on a scale | Standard Deviation 7.3 |
| Double-blind Adalimumab EOW | Swollen Joint Count (SJC68): Change From Baseline to Week 12 | Week 12 | 3.2 units on a scale | Standard Deviation 7.27 |
| Double-blind Adalimumab EOW | Swollen Joint Count (SJC68): Change From Baseline to Week 12 | Change from Baseline to Week 12 | -3.5 units on a scale | Standard Deviation 5.61 |
p-value: =0.50995% CI: [-4.49, 2.26]1-way ANOVA
Secondary
Tender Joint Count (TJC72): Change From Baseline to Week 12
Seventy-two joints were assessed by pressure on physical examination. Joint tenderness was classified as either present or absent. Scores range from 0 to 72, with higher scores representing higher disease activity. Baseline is defined as the last nonmissing value prior to the first dose of study drug. LOCF was used.
Time frame: Baseline and Week 12
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Double-blind Placebo EOW | Tender Joint Count (TJC72): Change From Baseline to Week 12 | Baseline | 11.9 units on a scale | Standard Deviation 9.34 |
| Double-blind Placebo EOW | Tender Joint Count (TJC72): Change From Baseline to Week 12 | Week 12 | 7.5 units on a scale | Standard Deviation 8.06 |
| Double-blind Placebo EOW | Tender Joint Count (TJC72): Change From Baseline to Week 12 | Change from Baseline to Week 12 | -4.5 units on a scale | Standard Deviation 8.97 |
| Double-blind Adalimumab EOW | Tender Joint Count (TJC72): Change From Baseline to Week 12 | Baseline | 13.4 units on a scale | Standard Deviation 10.49 |
| Double-blind Adalimumab EOW | Tender Joint Count (TJC72): Change From Baseline to Week 12 | Week 12 | 5.5 units on a scale | Standard Deviation 8.77 |
| Double-blind Adalimumab EOW | Tender Joint Count (TJC72): Change From Baseline to Week 12 | Change from Baseline to Week 12 | -7.9 units on a scale | Standard Deviation 8.25 |
p-value: =0.20995% CI: [-8.78, 1.97]1-way ANOVA