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Efficacy and Safety Study of ABP 501 Compared to Adalimumab in Subjects With Moderate to Severe Rheumatoid Arthritis

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ClinicalTrials.gov Identifier: NCT01970475
Recruitment Status : Completed
First Posted : October 28, 2013
Results First Posted : December 13, 2016
Last Update Posted : December 13, 2016
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Arthritis, Rheumatoid
Interventions Biological: ABP 501
Biological: Adalimumab
Enrollment 526

Recruitment Details

This study was conducted at 92 centers in 12 countries in Europe, North America and Latin America.

The first participant enrolled on 24 October 2013 and the last participant enrolled on 26 May 2014.

Pre-assignment Details Participants were randomized 1:1 to receive either ABP 501 or adalimumab at 40 mg every 2 weeks for 22 weeks. Randomization was stratified by geographic region and prior biologic use for rheumatoid arthritis (capped at 40% of the study population).
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22. Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Period Title: Overall Study
Started 264 262
Completed 243 251
Not Completed 21 11
Reason Not Completed
Withdrawal by Subject             11             6
Adverse Event             7             3
Lost to Follow-up             2             2
Protocol Violation             1             0
Arm/Group Title ABP 501 Adalimumab Total
Hide Arm/Group Description Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22. Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22. Total of all reporting groups
Overall Number of Baseline Participants 264 262 526
Hide Baseline Analysis Population Description
The full analysis set (all randomized participants)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 264 participants 262 participants 526 participants
55.4  (11.88) 56.3  (11.47) 55.9  (11.67)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 264 participants 262 participants 526 participants
< 65 years 205 197 402
≥ 65 years 59 65 124
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 264 participants 262 participants 526 participants
Female
214
  81.1%
212
  80.9%
426
  81.0%
Male
50
  18.9%
50
  19.1%
100
  19.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 264 participants 262 participants 526 participants
White 251 249 500
Black or African American 9 12 21
Asian 3 0 3
American Indian or Alaska Native 0 0 0
Native Hawaiian or Other Pacific Islander 0 0 0
Other 1 1 2
Ethnicity  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 264 participants 262 participants 526 participants
Hispanic or Latino 33 25 58
Not Hispanic or Latino 230 236 466
Not Allowed to Collect 1 1 2
Geographic Region  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 264 participants 262 participants 526 participants
Eastern Europe 169 168 337
Western Europe 22 20 42
North America 72 72 144
Latin America 1 2 3
Prior Biological Use for Rheumatoid Arthritis (RA)  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 264 participants 262 participants 526 participants
Yes 71 74 145
No 193 188 381
Duration of RA  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 264 participants 262 participants 526 participants
9.41  (8.076) 9.37  (8.047) 9.39  (8.054)
Swollen Joint Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Swollen joints
Number Analyzed 264 participants 262 participants 526 participants
14.7  (9.05) 14.1  (7.98) 14.4  (8.53)
[1]
Measure Description: Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination.
Tender Joint Count   [1] 
Mean (Standard Deviation)
Unit of measure:  Tender joints
Number Analyzed 264 participants 262 participants 526 participants
24.3  (14.35) 23.9  (13.49) 24.1  (13.92)
[1]
Measure Description: Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination.
Subject Global Health Assessment   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 264 participants 262 participants 526 participants
6.5  (1.92) 6.6  (1.86) 6.5  (1.89)
[1]
Measure Description: The participant's overall assessment of their disease activity in the past week on a 0 to 10 horizontal scale. The left-hand extreme of the scale was described as "no RA activity at all" (symptom-free and no arthritis symptoms; score = 0) and the right-hand extreme as "worst RA activity imaginable" (maximum arthritis disease activity; score = 10).
Investigator Global Health Assessment   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 264 participants 262 participants 526 participants
6.8  (1.29) 6.7  (1.59) 6.8  (1.45)
[1]
Measure Description: The Investigator's assessment of the participant's current disease activity on a 0 to 10 horizontal scale. The left-hand extreme of the scale was described as "no activity at all" (symptom-free and no arthritis symptoms; score = 0) and the right-hand extreme as "worst activity imaginable" (maximum arthritis disease activity; score = 10).
Subject's Assessment of Disease Related Pain   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 264 participants 262 participants 526 participants
58.3  (21.82) 60.6  (22.37) 59.5  (22.11)
[1]
Measure Description: The participant's assessment of their current level of pain on a 100 mm horizontal visual analogue scale (VAS). The left-hand extreme of the line was described as "no pain at all" (score = 0) and the right-hand extreme as "worst pain imaginable" (score = 100).
Health Assessment Questionnaire-Disability Index (HAQ-DI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 264 participants 262 participants 526 participants
1.4819  (0.61715) 1.4976  (0.64743) 1.4897  (0.63186)
[1]
Measure Description:

The HAQ-DI questionnaire asks participants to rate their level of difficulty on daily activities as well as their use of aids, devices, or help from another person for these activities and disabilities. Responses are scored from 0 indicating no difficulty to 3 indicating inability to perform a task in that area. The overall score is the average of each of the 8 category scores and ranges from 0 (no disability) to 3 (very severe, high-dependency disability).

Data are available for 263 and 261 participants in each group respectively.

C-reactive Protein  
Mean (Standard Deviation)
Unit of measure:  mg/L
Number Analyzed 264 participants 262 participants 526 participants
13.881  (20.6870) 14.678  (19.3848) 14.278  (20.0338)
Disease Activity Score 28-C-Reactive Protein (DAS28-CRP)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 264 participants 262 participants 526 participants
5.66  (0.918) 5.68  (0.911) 5.67  (0.914)
[1]
Measure Description:

The DAS28-CRP is a composite score to measure disease activity in patients with RA, derived from the following variables:

  • The number of swollen and tender joints (28-joint count);
  • C-reactive protein (CRP);
  • Patient's global assessment of disease activity assessed on a scale from 0 to 100 transformed from the result measured on a horizontal scale from 0 (no RA activity at all) to 10 (worst RA activity imaginable).

DAS28-CRP scores range from approximately zero to ten. Higher scores indicate higher disease activity.

Data are available for 264 and 261 participants in each group respectively.

1.Primary Outcome
Title Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24
Hide Description

A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 20% improvement in tender joint count;
  • ≥ 20% improvement in swollen joint count; and
  • ≥ 20% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Physician's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • C-Reactive Protein level.
Time Frame Baseline and Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The full analysis set (all randomized participants); missing values were imputed using the last observation carried forward (LOCF) method for participants with at least 1 postbaseline value.
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description:
Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Overall Number of Participants Analyzed 260 261
Measure Type: Number
Unit of Measure: percentage of participants
74.6 72.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ABP 501, Adalimumab
Comments The study hypothesis was that there were no clinically meaningful differences between ABP 501 and adalimumab in risk ratio (RR) of ACR20 at week 24.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The hypothesis was tested by comparing the 2-sided 90% confidence interval (CI) of the RR of ACR20 at week 24 between ABP 501 and adalimumab with an equivalence margin of (0.738, 1/0.738).
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.039
Confidence Interval (2-Sided) 90%
0.954 to 1.133
Estimation Comments Based on a generalized linear model adjusted for geographic region and prior biological use for RA as covariates in the model.
2.Secondary Outcome
Title Change From Baseline in Disease Activity Score 28-C-reactive Protein (DAS28-CRP)
Hide Description

The DAS28-CRP is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables:

  • The number of swollen and tender joints assessed using the 28-joint count;
  • C-reactive protein (CRP) level
  • Patient's global assessment of disease activity assessed on a score from 0 to 100 transformed from the result measured on a horizontal scale from 0 (no RA activity at all) to 10 (worst RA activity imaginable).

The DAS28-CRP score ranges from approximately zero to ten. Higher DAS28-CRP scores indicate higher disease activity.

A repeated measures analysis with the DAS28-CRP change from baseline as the response and the stratification variables, visit, treatment, treatment-by-visit interaction and the baseline DAS28-CRP measurement as predictors in the model was performed.

Time Frame Baseline and weeks 2, 4, 8, 12, 18, and 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set with available data at each time point
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description:
Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Overall Number of Participants Analyzed 264 262
Least Squares Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 2 (n = 254, 252) -1.01  (0.891) -0.96  (0.890)
Week 4 (n = 255, 254) -1.45  (1.048) -1.42  (0.979)
Week 8 (n = 247, 255) -1.79  (1.075) -1.70  (1.093)
Week 12 (n = 245, 250) -2.04  (1.112) -1.93  (1.171)
Week 18 (n = 244, 250) -2.30  (1.184) -2.17  (1.189)
Week 24 (n = 243, 250) -2.32  (1.237) -2.32  (1.209)
3.Secondary Outcome
Title Percentage of Participants With an ACR20 Response at Week 2 and Week 8
Hide Description

A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 20% improvement in tender joint count;
  • ≥ 20% improvement in swollen joint count; and
  • ≥ 20% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Physician's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • C-Reactive Protein level.
Time Frame Baseline, week 2 and week 8
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set; LOCF imputation was used for participants with at least 1 postbaseline value (indicated by n).
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description:
Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Overall Number of Participants Analyzed 264 262
Measure Type: Number
Unit of Measure: percentage of participants
Week 2 (n = 254, 257) 35.4 24.5
Week 8 (n = 260, 261) 63.5 62.5
4.Secondary Outcome
Title Percentage of Participants With an ACR50 Response at Week 24
Hide Description

A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 50% improvement in tender joint count;
  • ≥ 50% improvement in swollen joint count; and
  • ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Physician's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • C-Reactive Protein level.
Time Frame Baseline and week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set with available data at week 24
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description:
Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Overall Number of Participants Analyzed 244 252
Measure Type: Number
Unit of Measure: percentage of participants
49.2 52.0
5.Secondary Outcome
Title Percentage of Participants With an ACR70 Response at Week 24
Hide Description

A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 70% improvement in tender joint count;
  • ≥ 70% improvement in swollen joint count; and
  • ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Physician's global assessment of disease activity (measured on a likert scale from 0 to 10);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • C-Reactive Protein level.
Time Frame Baseline and Week 24
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set with available data at week 24
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description:
Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Overall Number of Participants Analyzed 246 253
Measure Type: Number
Unit of Measure: percentage of participants
26.0 22.9
6.Secondary Outcome
Title Number of Participants With Adverse Events
Hide Description

Adverse events (AEs) were graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 according to the following scale:

1 = mild; 2 = moderate; 3 = severe; 4 = life-threatening; 5 = fatal. A treatment-related AE is defined as an event where the answer to the question “is there a reasonable possibility that the event may have been caused by the Investigational Medicinal Product” was yes.

A serious adverse event is defined as an AE that meets at least 1 of the following serious criteria:

  • fatal
  • life threatening (places the subject at immediate risk of death)
  • requires inpatient hospitalization or prolongation of existing hospitalization
  • results in persistent or significant disability/incapacity
  • congenital anomaly/birth defect
  • other medically important serious event.
Time Frame From the time of first treatment up to 28 days following the last dose of study treatment; 26 weeks.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set (all participants who received at least 1 dose of study drug)
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description:
Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Overall Number of Participants Analyzed 264 262
Measure Type: Number
Unit of Measure: participants
Any adverse event (AE) 132 143
Adverse event ≥ grade 3 9 17
Treatment-related adverse event (TRAE) 50 55
Treatment-related adverse event ≥ grade 3 3 2
Serious adverse event (SAE) 10 13
Treatment-related serious adverse event 4 1
AE leading to discontinuation of study drug 5 2
TRAE leading to discontinuation of study drug 4 1
AE leading to discontinuation from study 7 2
TRAE leading to discontinuation from study 5 0
7.Secondary Outcome
Title Percentage of Participants Who Developed Antibodies to ABP 501 or Adalimumab
Hide Description

Two validated assays were used to detect the presence of anti-drug antibodies. Samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against ABP 501 and adalimumab (Binding Antibody Assay). Samples confirmed to be positive for binding antibodies were subsequently tested in a non-cell based bioassay to determine neutralizing activity against ABP 501 or adalimumab (Neutralizing Antibody Assay).

Developing antibody incidence is defined as a negative or no antibody result at baseline and a positive antibody result at a post-baseline time point.

Time Frame Up to week 26
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants with at least 1 evaluable antibody test result (to either ABP 501 or adalimumab)
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description:
Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Overall Number of Participants Analyzed 264 262
Measure Type: Number
Unit of Measure: percentage of participants
Developing Binding Antibody 38.3 38.2
Developing Neutralizing Antibody 9.1 11.1
Time Frame From the time of first treatment but on or within 28 days following the last dose of study treatment; 26 weeks.
Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title ABP 501 Adalimumab
Hide Arm/Group Description Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22. Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
All-Cause Mortality
ABP 501 Adalimumab
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
ABP 501 Adalimumab
Affected / at Risk (%) Affected / at Risk (%)
Total   10/264 (3.79%)   13/262 (4.96%) 
Blood and lymphatic system disorders     
Lymphadenopathy  1  1/264 (0.38%)  0/262 (0.00%) 
Cardiac disorders     
Acute myocardial infarction  1  0/264 (0.00%)  1/262 (0.38%) 
Cardiac failure congestive  1  0/264 (0.00%)  1/262 (0.38%) 
Cardiopulmonary failure  1  1/264 (0.38%)  0/262 (0.00%) 
Myocardial infarction  1  0/264 (0.00%)  1/262 (0.38%) 
Wolff-Parkinson-White syndrome  1  0/264 (0.00%)  1/262 (0.38%) 
Gastrointestinal disorders     
Enterocolitis  1  1/264 (0.38%)  0/262 (0.00%) 
Large intestinal obstruction  1  0/264 (0.00%)  1/262 (0.38%) 
Immune system disorders     
Corneal graft rejection  1  0/264 (0.00%)  1/262 (0.38%) 
Hypersensitivity  1  1/264 (0.38%)  0/262 (0.00%) 
Infections and infestations     
Appendicitis perforated  1  1/264 (0.38%)  0/262 (0.00%) 
Arthritis bacterial  1  0/264 (0.00%)  1/262 (0.38%) 
Gastroenteritis  1  0/264 (0.00%)  1/262 (0.38%) 
Peritoneal abscess  1  1/264 (0.38%)  0/262 (0.00%) 
Pneumonia  1  1/264 (0.38%)  0/262 (0.00%) 
Pneumonia fungal  1  0/264 (0.00%)  1/262 (0.38%) 
Sepsis  1  2/264 (0.76%)  0/262 (0.00%) 
Injury, poisoning and procedural complications     
Humerus fracture  1  1/264 (0.38%)  0/262 (0.00%) 
Meniscus injury  1  1/264 (0.38%)  0/262 (0.00%) 
Thoracic vertebral fracture  1  0/264 (0.00%)  1/262 (0.38%) 
Musculoskeletal and connective tissue disorders     
Foot deformity  1  0/264 (0.00%)  1/262 (0.38%) 
Osteoarthritis  1  0/264 (0.00%)  1/262 (0.38%) 
Pseudarthrosis  1  0/264 (0.00%)  1/262 (0.38%) 
Nervous system disorders     
Cerebrovascular accident  1  1/264 (0.38%)  0/262 (0.00%) 
Vascular disorders     
Hypertension  1  1/264 (0.38%)  0/262 (0.00%) 
Venous thrombosis limb  1  1/264 (0.38%)  0/262 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
ABP 501 Adalimumab
Affected / at Risk (%) Affected / at Risk (%)
Total   17/264 (6.44%)   19/262 (7.25%) 
Infections and infestations     
Nasopharyngitis  1  17/264 (6.44%)  19/262 (7.25%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01970475     History of Changes
Other Study ID Numbers: 20120262
2013-000525-31 ( EudraCT Number )
First Submitted: October 23, 2013
First Posted: October 28, 2013
Results First Submitted: October 20, 2016
Results First Posted: December 13, 2016
Last Update Posted: December 13, 2016