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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00950989
• Collaborator: (none)
• Enrollment: 252
• Arms: 4
• Actual Duration (Months): 13.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Brodalumab; Drug: Placebo; Drug: Methotrexate; Dietary Supplement: folic acid	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 252 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Dec 30, 2009
• Actual Primary Completion Date: Feb 11, 2011
• Actual Study Completion Date: Feb 11, 2011

Arms and Interventions

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: Brodalumab; 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10; Other Names: AMG 827 ; 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 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: Brodalumab; 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10; Other Names: AMG 827 ; 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
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: Brodalumab; 3 single subcutaneous (SC) injections at day 1 and weeks 1, 2, 4, 6, 8, and 10; Other Names: AMG 827 ; 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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 [Baseline, 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.

Secondary Outcome Measures

1. Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 [Baseline, 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.

2. Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 [Baseline, 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.

3. Disease Activity Score 28 (DAS28) at Week 12 [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.

4. Number of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation [From first dose of study drug until the end of study; median (min, max) duration was 113 days (8, 132).]

   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.

5. 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]

6. 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]

7. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

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.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00950989
• Other Study ID Numbers: 20090061
• First Posted: Aug 3, 2009
• Last Update Posted: Dec 21, 2021
• Last Verified: Nov 1, 2021

• Keywords provided by Amgen: Autoimmune Diseases; Musculoskeletal Diseases; Joint Diseases; Arthritis; Connective Tissue Diseases; Arthritis, Rheumatoid; Rheumatic Diseases
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Folic Acid; Methotrexate; Brodalumab

Study Results

Participant Flow

Recruitment Details	This study was conducted in the following countries: Bulgaria, Canada, Czech Republic, Hungary, Latvia, Mexico, Poland, United Kingdom, United States.
Pre-assignment Detail	Participants were randomized in a 1:1:1:1 ratio to receive brodalumab (doses of 70, 140, or 210 mg) or placebo. Randomization was stratified by sex with enrollment of women limited to 200 participants.

Arm/Group Title	Placebo	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Period Title: Overall Study
STARTED	63	63	63	63
COMPLETED	59	60	60	63
NOT COMPLETED	4	3	3	0

Baseline Characteristics

Arm/Group Title	Placebo	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg	Total
Arm/Group Description	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).	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).	Total of all reporting groups
Overall Participants	63	63	63	63	252
Age, Customized (Count of Participants)
< 65 years	57 90.5%	60 95.2%	53 84.1%	58 92.1%	228 90.5%
>= 65 years	6 9.5%	3 4.8%	10 15.9%	5 7.9%	24 9.5%
Sex: Female, Male (Count of Participants)
Female	51 81%	50 79.4%	49 77.8%	50 79.4%	200 79.4%
Male	12 19%	13 20.6%	14 22.2%	13 20.6%	52 20.6%
Race/Ethnicity, Customized (Count of Participants)
White or Caucasian	48 76.2%	53 84.1%	50 79.4%	56 88.9%	207 82.1%
Black or African American	1 1.6%	1 1.6%	1 1.6%	0 0%	3 1.2%
Hispanic or Latino	14 22.2%	8 12.7%	12 19%	6 9.5%	40 15.9%
Asian	0 0%	1 1.6%	0 0%	1 1.6%	2 0.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12
Description	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.
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants with an assessment. Non-responder imputation.

Arm/Group Title	Placebo	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	63	63	63	63
Number [percentage of participants]	12.7 20.2%	15.9 25.2%	15.9 25.2%	9.5 15.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 70 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.598
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; -9.0 to 15.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 70 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.993
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 140 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; -9.0 to 15.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 140 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.740
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 210 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.572
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) 95%; -14.1 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 210 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.572
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

2. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
Description	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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants with an assessment. Non-responder imputation.

Arm/Group Title	Placebo	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	63	63	63	63
Number [percentage of partcipants]	42.9	39.7	36.5	46.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 70 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.728
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) 95%; -20.4 to 14.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 70 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.993
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 140 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.412
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-6.3
	Confidence Interval	(2-Sided) 95%; -23.4 to 10.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 140 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.740
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedures
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 210 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.740
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; -14.2 to 20.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 210 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.993
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

3. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12
Description	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.
Time Frame	Baseline, week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants with an assessment. Non-responder imputation.

Arm/Group Title	Placebo	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	63	63	63	63
Number [percentage of participants]	3.2 5.1%	3.2 5.1%	3.2 5.1%	0.0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 70 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.984
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -6.1 to 6.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 70 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.993
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 140 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.993
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -6.1 to 6.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 140 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.993
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 210 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.159
	Comments	P-value is nominal p-value without multiplicity adjustment based on Cochran-Mantel-Haenszel test adjusting for sex.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	-3.2
	Confidence Interval	(2-Sided) 95%; -7.5 to 1.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 210 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.797
	Comments	Adjusted p-value is based on a combination of sequential testing and the Hommel procedure to control the overall significance level for all the comparisons.
	Method	Sequential testing + Hommel procedure
	Comments

4. Secondary Outcome

Title	Disease Activity Score 28 (DAS28) at Week 12
Description	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.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all randomized participants with an assessment. Last observation carried forward (LOCF).

Arm/Group Title	Placebo	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	63	61	63	63
Least Squares Mean (Standard Error) [score on a scale]	5.0 (0.2)	4.9 (0.2)	5.1 (0.2)	5.1 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 70 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.459
	Comments	P-value is nominal without multiplicity adjustment based on ANCOVA model adjusting for sex and baseline DAS28 score.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean of difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.7 to 0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 140 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.906
	Comments	P-value is nominal without multiplicity adjustment based on ANCOVA model adjusting for sex and baseline DAS28 score.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean of difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brodalumab 210 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.849
	Comments	P-value is nominal without multiplicity adjustment based on ANCOVA model adjusting for sex and baseline DAS28 score.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean of difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation
Description	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.
Time Frame	From first dose of study drug until the end of study; median (min, max) duration was 113 days (8, 132).

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	63	63	63	63
AEs	32 50.8%	32 50.8%	40 63.5%	32 50.8%
SAEs	2 3.2%	1 1.6%	1 1.6%	3 4.8%
Fatal AEs	0 0%	0 0%	1 1.6%	0 0%
AEs leading to Study Discontinuation	2 3.2%	1 1.6%	2 3.2%	0 0%
AEs leading to Study Drug Discontinuation	1 1.6%	1 1.6%	1 1.6%	2 3.2%
CTCAE Grades 3, 4, 5 AEs	4 6.3%	3 4.8%	2 3.2%	4 6.3%
AEs Related to Study Drug	12 19%	8 12.7%	14 22.2%	11 17.5%
SAEs Related to Study Drug	0 0%	0 0%	0 0%	0 0%
Fatal AEs Related to Study Drug	0 0%	0 0%	0 0%	0 0%
AEs Related to Study Drug Leading to Study Discontinuation	1 1.6%	1 1.6%	0 0%	0 0%
AEs Related to Study Drug Leading to Study Drug Discontinuation	0 0%	1 1.6%	0 0%	2 3.2%
CTCAE Grades 3, 4, 5 AEs Related to Study Drug	0 0%	1 1.6%	0 0%	0 0%

6. Secondary Outcome

Title	Pharmacokinetics (PK) of Brodalumab: Maximum Observed Concentration (Cmax)
Time Frame	Week 8: Day 59-Day 61 (44-100 hours post-dose), Day 64 (160-176 hours post-dose), Week 10: pre-dose

Outcome Measure Data

Analysis Population Description

Participants who received brodalumab with an evaluable PK measurement.

Arm/Group Title	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	15	13	12
Mean (Standard Deviation) [µg/mL]	3.02 (1.61)	7.85 (4.37)	17.9 (12.8)

7. Secondary Outcome

Title	PK of Brodalumab: Time to Maximum Observed Concentration (Tmax)
Time Frame	Week 8: Day 59-Day 61 (44-100 hours post-dose), Day 64 (160-176 hours post-dose), Week 10: pre-dose

Outcome Measure Data

Analysis Population Description

Participants who received brodalumab with an evaluable PK measurement.

Arm/Group Title	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	15	13	12
Median (Full Range) [days]	1.94	2.00	1.96

8. Secondary Outcome

Title	PK of Brodalumab: Area Under the Curve During the Dosing Interval (AUCtau)
Time Frame	Week 8: Day 59-Day 61 (44-100 hours post-dose), Day 64 (160-176 hours post-dose), Week 10: pre-dose

Outcome Measure Data

Analysis Population Description

Participants who received AMG 827 with an evaluable PK measurement.

Arm/Group Title	Brodalumab 70 mg	Brodalumab 140 mg	Brodalumab 210 mg
Arm/Group Description	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).	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 methotrexate and folic acid supplementation (at least 5 mg per week).	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).
Measure Participants	15	13	12
Mean (Standard Deviation) [µg*day/mL]	18.1 (15.2)	73.3 (52.7)	199 (161)

Adverse Events

Time Frame	From first dose of study drug until the end of study; median (min, max) duration was 113 days (8, 132).
Arm/Group Title	Placebo		Brodalumab 70 mg		Brodalumab 140 mg		Brodalumab 210 mg
Arm/Group Description	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).		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).		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).		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).
All Cause Mortality
	Placebo		Brodalumab 70 mg		Brodalumab 140 mg		Brodalumab 210 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Brodalumab 70 mg		Brodalumab 140 mg		Brodalumab 210 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/63 (3.2%)		1/63 (1.6%)		1/63 (1.6%)		3/63 (4.8%)
Cardiac disorders
Cardiopulmonary failure	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/63 (0%)
Eye disorders
Blepharitis	0/63 (0%)		1/63 (1.6%)		0/63 (0%)		0/63 (0%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	0/63 (0%)		0/63 (0%)		0/63 (0%)		1/63 (1.6%)
Tibia fracture	1/63 (1.6%)		0/63 (0%)		0/63 (0%)		0/63 (0%)
Musculoskeletal and connective tissue disorders
Osteoporotic fracture	0/63 (0%)		0/63 (0%)		0/63 (0%)		1/63 (1.6%)
Rheumatoid arthritis	1/63 (1.6%)		0/63 (0%)		0/63 (0%)		0/63 (0%)
Psychiatric disorders
Suicide attempt	0/63 (0%)		0/63 (0%)		0/63 (0%)		1/63 (1.6%)
Vascular disorders
Thrombosis	0/63 (0%)		0/63 (0%)		0/63 (0%)		1/63 (1.6%)
Other (Not Including Serious) Adverse Events
	Placebo		Brodalumab 70 mg		Brodalumab 140 mg		Brodalumab 210 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/63 (28.6%)		19/63 (30.2%)		25/63 (39.7%)		12/63 (19%)
General disorders
Injection site pain	4/63 (6.3%)		2/63 (3.2%)		2/63 (3.2%)		2/63 (3.2%)
Infections and infestations
Nasopharyngitis	2/63 (3.2%)		3/63 (4.8%)		4/63 (6.3%)		4/63 (6.3%)
Upper respiratory tract infection	1/63 (1.6%)		4/63 (6.3%)		5/63 (7.9%)		3/63 (4.8%)
Urinary tract infection	1/63 (1.6%)		2/63 (3.2%)		5/63 (7.9%)		4/63 (6.3%)
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis	5/63 (7.9%)		4/63 (6.3%)		7/63 (11.1%)		0/63 (0%)
Nervous system disorders
Headache	4/63 (6.3%)		3/63 (4.8%)		3/63 (4.8%)		1/63 (1.6%)
Respiratory, thoracic and mediastinal disorders
Cough	4/63 (6.3%)		2/63 (3.2%)		2/63 (3.2%)		1/63 (1.6%)
Vascular disorders
Hypertension	4/63 (6.3%)		2/63 (3.2%)		3/63 (4.8%)		2/63 (3.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.