Brodalumab (AMG 827) in Rheumatoid Arthritis (RA) Participants With Inadequate Response to Methotrexate

Study Overview
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Brief Summary
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Study in participants with RA who have an inadequate response to methotrexate.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multiple-dose Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 827 in Subjects With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Brodalumab
* Drug: Placebo
* Drug: Methotrexate
* Dietary Supplement: folic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active RA for least 6 months Current RA defined as ≥ 6 swollen joints (out of 66 joints examined) and ≥ 8 tender/painful joints (out of 68 joints examined) at screening and baseline (swollen and tender/painful joint count must not include distal interphalangeal joints) and at least 1 of the following at screening: Erythrocyte sedimentation rate ≥ 28 mm or C-reactive protein > 15 mg/L At least 1 of the following at screening: Rheumatoid factor positive or Anti-cyclic citrullinated peptide antibody positive Currently taking methotrexate for ≥ 12 weeks and on a stable dose of methotrexate at 15 to 25 mg weekly for ≥ 4 weeks at day -1. Exclusion Criteria: Prosthetic joint infection within 5 years of screening or native joint infection within 1 year of screening Class IV RA Felty's syndrome Presence of serious infection Significant concurrent medical conditions Pregnant or breast feeding Significant Laboratory abnormalities Any disease-modifying anti-rheumatic drug (DMARD) other than methotrexate within 28 days Leflunomide or live vaccines within 3 months Previous use of any experimental or commercially available biologic DMARD

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo on day 1 and weeks 1, 2, 4, 6, 8, and 10 for a total of 7 doses plus a stable weekly dose of methotrexate and folic acid supplementation (at least 5 mg per week). | Drug: Placebo<br>* 3 single SC injections at day 1 and weeks 1, 2, 4, 6, 8, and 10<br>Drug: Methotrexate<br>* Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.<br>Dietary Supplement: folic acid<br>* at least 5 mg per week<br>|
| Experimental: Brodalumab 70 mg<br>70 mg brodalumab on day 1 and weeks 1, 2, 4, 6, 8, and 10 for a total of 7 doses plus a stable weekly dose of methotrexate and folic acid supplementation (at least 5 mg per week). | Drug: Brodalumab<br>* 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10<br>* Other names: AMG 827;Drug: Methotrexate<br>* Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.<br>Dietary Supplement: folic acid<br>* at least 5 mg per week<br>|
| Experimental: Brodalumab 140 mg<br>140 mg brodalumab on day 1 and weeks 1, 2, 4, 6, 8, and 10 for a total of 7 doses plus a stable weekly dose of methotrexateand folic acid supplementation (at least 5 mg per week). | Drug: Brodalumab<br>* 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10<br>* Other names: AMG 827;Drug: Methotrexate<br>* Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.<br>Dietary Supplement: folic acid<br>* at least 5 mg per week<br>|
| Placebo Comparator: Brodalumab 210 mg<br>210 mg brodalumab on day 1 and weeks 1, 2, 4, 6, 8, and 10 for a total of 7 doses plus a stable weekly dose of methotrexate and folic acid supplementation (at least 5 mg per week). | Drug: Brodalumab<br>* 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10<br>* Other names: AMG 827;Drug: Methotrexate<br>* Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.<br>Dietary Supplement: folic acid<br>* at least 5 mg per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 | A positive ACR50 response is defined if the following 3 criteria for improvement from baseline were met: 50% improvement in 68 tender joint count; 50% improvement in 66 swollen joint count; and 50% improvement in at least 3 of the 5 following parameters: Patient's assessment of joint pain (measured on a 100 mm visual analog scale [VAS]), Patient's global assessment of disease activity (measured on a 0-10 Likert scale), Physician's global assessment of disease activity (measured on a 0-10 Likert scale), Patient's self assessment of disability (Health Assessment Questionnaire - Disability Index [HAQ-DI]), Acute phase reactant: erythrocyte sedimentation rate (ESR) or C-Reactive Protein (CRP), whichever has bigger improvement. | Baseline, week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 | A positive ACR20 response is defined if the following 3 criteria for improvement from baseline were met: 20% improvement in 68 tender joint count; 20% improvement in 66 swollen joint count; and 20% improvement in at least 3 of the 5 following parameters: Patient's assessment of joint pain (measured on a 100 mm visual analog scale [VAS]), Patient's global assessment of disease activity (measured on a 0-10 Likert scale), Physician's global assessment of disease activity (measured on a 0-10 Likert scale), Patient's self assessment of disability (Health Assessment Questionnaire - Disability Index [HAQ-DI]), Acute phase reactant: erythrocyte sedimentation rate (ESR) or C-Reactive Protein (CRP), whichever has bigger improvement. | Baseline, Week 12 | 
| Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 | A positive ACR70 response is defined if the following 3 criteria for improvement from baseline were met: 70% improvement in 68 tender joint count; 70% improvement in 66 swollen joint count; and 70% improvement in at least 3 of the 5 following parameters: Patient's assessment of joint pain (measured on a 100 mm visual analog scale [VAS]), Patient's global assessment of disease activity (measured on a 0-10 Likert scale), Physician's global assessment of disease activity (measured on a 0-10 Likert scale), Patient's self assessment of disability (Health Assessment Questionnaire - Disability Index [HAQ-DI]), Acute phase reactant: erythrocyte sedimentation rate (ESR) or C-Reactive Protein (CRP), whichever has bigger improvement. | Baseline, week 12 | 
| Disease Activity Score 28 (DAS28) at Week 12 | The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: • The number of tender joints assessed using the 28-jount count and number of swollen joints assessed using the 28-joint count; • Erythrocyte sedimentation rate (ESR); • Patient's global assessment of disease activity (measured on a 0-10 Likert scale). The DAS28 score ranges from 0 to 10, with higher scores indicating more severe disease activity. | Week 12 | 
| Number of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation | AEs are defined as any untoward medical occurrence, that does not necessarily have a causal relationship with this treatment. SAEs are defined as an AE that: is fatal; is life threatening (places the subject at immediate risk of death); requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; other significant medical hazard. The severity of events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0: mild=grade 1, moderate=grade 2, severe=grade 3, life-threatening=grade 4, death=grade 5. | From first dose of study drug until the end of study; median (min, max) duration was 113 days (8, 132). | 
| Pharmacokinetics (PK) of Brodalumab: Maximum Observed Concentration (Cmax) |  | Week 8: Day 59-Day 61 (44-100 hours post-dose), Day 64 (160-176 hours post-dose), Week 10: pre-dose | 
| PK of Brodalumab: Time to Maximum Observed Concentration (Tmax) |  | Week 8: Day 59-Day 61 (44-100 hours post-dose), Day 64 (160-176 hours post-dose), Week 10: pre-dose | 
| PK of Brodalumab: Area Under the Curve During the Dosing Interval (AUCtau) |  | Week 8: Day 59-Day 61 (44-100 hours post-dose), Day 64 (160-176 hours post-dose), Week 10: pre-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmune Diseases, Musculoskeletal Diseases, Joint Diseases, Arthritis, Connective Tissue Diseases, Arthritis, Rheumatoid, Rheumatic Diseases