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

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

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

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Placebo; Drug: Methotrexate; Dietary supplement: folic acid; Drug: Brodalumab

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; 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; 3 single SC injections at day 1 and weeks 1, 2, 4, 6, 8, and 10; Drug: Methotrexate; Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.; Dietary supplement: folic acid; at least 5 mg per week
EXPERIMENTAL: Brodalumab 70 mg; 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: Methotrexate; Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.; Dietary supplement: folic acid; at least 5 mg per week; Drug: Brodalumab; 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10; Other Names: AMG 827
EXPERIMENTAL: Brodalumab 140 mg; 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: Methotrexate; Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.; Dietary supplement: folic acid; at least 5 mg per week; Drug: Brodalumab; 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10; Other Names: AMG 827
PLACEBO_COMPARATOR: Brodalumab 210 mg; 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: Methotrexate; Two methotrexate dose adjustments were allowed in the event of methotrexate toxicity, however, doses < 7.5 mg/week necessitated discontinuation from study.; Dietary supplement: folic acid; at least 5 mg per week; Drug: Brodalumab; 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10; Other Names: AMG 827

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Pavelka K, Chon Y, Newmark R, Lin SL, Baumgartner S, Erondu N. A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate. J Rheumatol. 2015 Jun;42(6):912-9. doi: 10.3899/jrheum.141271. Epub 2015 Apr 15.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 30, 2009
• Primary Completion (ACTUAL): February 11, 2011
• Study Completion (ACTUAL): February 11, 2011

Study Registration Dates

• First Submitted: July 30, 2009
• First Submitted That Met QC Criteria: July 30, 2009
• First Posted (ESTIMATE): August 3, 2009

Study Record Updates

• Last Update Posted (ACTUAL): December 21, 2021
• Last Update Submitted That Met QC Criteria: November 22, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Arthritis; Connective Tissue Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis, Rheumatoid
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Micronutrients; Vitamins; Reproductive Control Agents; Vitamin B Complex; Hematinics; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Folic Acid; Brodalumab
• Other Study ID Numbers: 20090061