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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01970475
First Posted: October 28, 2013
Last Update Posted: December 13, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Amgen
Results First Submitted: October 20, 2016  
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

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

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
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Participant Flow:   Overall Study
    ABP 501   Adalimumab
STARTED   264   262 
COMPLETED   243   251 
NOT COMPLETED   21   11 
Withdrawal by Subject                11                6 
Adverse Event                7                3 
Lost to Follow-up                2                2 
Protocol Violation                1                0 



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The full analysis set (all randomized participants)

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Total Total of all reporting groups

Baseline Measures
   ABP 501   Adalimumab   Total 
Overall Participants Analyzed 
[Units: Participants]
 264   262   526 
Age 
[Units: Years]
Mean (Standard Deviation)
 55.4  (11.88)   56.3  (11.47)   55.9  (11.67) 
Age, Customized 
[Units: Participants]
     
< 65 years   205   197   402 
≥ 65 years   59   65   124 
Gender 
[Units: Participants]
     
Female   214   212   426 
Male   50   50   100 
Race/Ethnicity, Customized 
[Units: 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 
[Units: Participants]
     
Hispanic or Latino   33   25   58 
Not Hispanic or Latino   230   236   466 
Not Allowed to Collect   1   1   2 
Geographic Region 
[Units: 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) 
[Units: Participants]
     
Yes   71   74   145 
No   193   188   381 
Duration of RA 
[Units: Years]
Mean (Standard Deviation)
 9.41  (8.076)   9.37  (8.047)   9.39  (8.054) 
Swollen Joint Count [1] 
[Units: Swollen joints]
Mean (Standard Deviation)
 14.7  (9.05)   14.1  (7.98)   14.4  (8.53) 
[1] Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination.
Tender Joint Count [1] 
[Units: Tender joints]
Mean (Standard Deviation)
 24.3  (14.35)   23.9  (13.49)   24.1  (13.92) 
[1] Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination.
Subject Global Health Assessment [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 6.5  (1.92)   6.6  (1.86)   6.5  (1.89) 
[1] 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] 
[Units: Units on a scale]
Mean (Standard Deviation)
 6.8  (1.29)   6.7  (1.59)   6.8  (1.45) 
[1] 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] 
[Units: Units on a scale]
Mean (Standard Deviation)
 58.3  (21.82)   60.6  (22.37)   59.5  (22.11) 
[1] 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] 
[Units: Units on a scale]
Mean (Standard Deviation)
 1.4819  (0.61715)   1.4976  (0.64743)   1.4897  (0.63186) 
[1]

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 
[Units: mg/L]
Mean (Standard Deviation)
 13.881  (20.6870)   14.678  (19.3848)   14.278  (20.0338) 
Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 5.66  (0.918)   5.68  (0.911)   5.67  (0.914) 
[1]

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.



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24   [ Time Frame: Baseline and Week 24 ]

Measure Type Primary
Measure Title Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Measured Values
   ABP 501   Adalimumab 
Participants Analyzed 
[Units: Participants]
 260   261 
Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24 
[Units: Percentage of participants]
 74.6   72.4 


Statistical Analysis 1 for Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Week 24
Groups [1] All groups
Statistical Test Type [2] Non-Inferiority or Equivalence
Risk Ratio (RR) [3] 1.039
90% Confidence Interval 0.954 to 1.133
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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).
[3] Other relevant estimation information:
  Based on a generalized linear model adjusted for geographic region and prior biological use for RA as covariates in the model.



2.  Secondary:   Change From Baseline in Disease Activity Score 28-C-reactive Protein (DAS28-CRP)   [ Time Frame: Baseline and weeks 2, 4, 8, 12, 18, and 24 ]

Measure Type Secondary
Measure Title Change From Baseline in Disease Activity Score 28-C-reactive Protein (DAS28-CRP)
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set with available data at each time point

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Measured Values
   ABP 501   Adalimumab 
Participants Analyzed 
[Units: Participants]
 264   262 
Change From Baseline in Disease Activity Score 28-C-reactive Protein (DAS28-CRP) 
[Units: Units on a scale]
Least Squares Mean (Standard Deviation)
   
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) 

No statistical analysis provided for Change From Baseline in Disease Activity Score 28-C-reactive Protein (DAS28-CRP)



3.  Secondary:   Percentage of Participants With an ACR20 Response at Week 2 and Week 8   [ Time Frame: Baseline, week 2 and week 8 ]

Measure Type Secondary
Measure Title Percentage of Participants With an ACR20 Response at Week 2 and Week 8
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set; LOCF imputation was used for participants with at least 1 postbaseline value (indicated by n).

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Measured Values
   ABP 501   Adalimumab 
Participants Analyzed 
[Units: Participants]
 264   262 
Percentage of Participants With an ACR20 Response at Week 2 and Week 8 
[Units: Percentage of participants]
   
Week 2 (n = 254, 257)   35.4   24.5 
Week 8 (n = 260, 261)   63.5   62.5 

No statistical analysis provided for Percentage of Participants With an ACR20 Response at Week 2 and Week 8



4.  Secondary:   Percentage of Participants With an ACR50 Response at Week 24   [ Time Frame: Baseline and week 24 ]

Measure Type Secondary
Measure Title Percentage of Participants With an ACR50 Response at Week 24
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set with available data at week 24

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Measured Values
   ABP 501   Adalimumab 
Participants Analyzed 
[Units: Participants]
 244   252 
Percentage of Participants With an ACR50 Response at Week 24 
[Units: Percentage of participants]
 49.2   52.0 

No statistical analysis provided for Percentage of Participants With an ACR50 Response at Week 24



5.  Secondary:   Percentage of Participants With an ACR70 Response at Week 24   [ Time Frame: Baseline and Week 24 ]

Measure Type Secondary
Measure Title Percentage of Participants With an ACR70 Response at Week 24
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full analysis set with available data at week 24

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Measured Values
   ABP 501   Adalimumab 
Participants Analyzed 
[Units: Participants]
 246   253 
Percentage of Participants With an ACR70 Response at Week 24 
[Units: Percentage of participants]
 26.0   22.9 

No statistical analysis provided for Percentage of Participants With an ACR70 Response at Week 24



6.  Secondary:   Number of Participants With Adverse Events   [ Time Frame: From the time of first treatment up to 28 days following the last dose of study treatment; 26 weeks. ]

Measure Type Secondary
Measure Title Number of Participants With Adverse Events
Measure 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.  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set (all participants who received at least 1 dose of study drug)

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Measured Values
   ABP 501   Adalimumab 
Participants Analyzed 
[Units: Participants]
 264   262 
Number of Participants With Adverse Events 
[Units: 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 

No statistical analysis provided for Number of Participants With Adverse Events



7.  Secondary:   Percentage of Participants Who Developed Antibodies to ABP 501 or Adalimumab   [ Time Frame: Up to week 26 ]

Measure Type Secondary
Measure Title Percentage of Participants Who Developed Antibodies to ABP 501 or Adalimumab
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants with at least 1 evaluable antibody test result (to either ABP 501 or adalimumab)

Reporting Groups
  Description
ABP 501 Participants received ABP 501 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.
Adalimumab Participants received adalimumab 40 mg subcutaneously on day 1 and every 2 weeks thereafter until week 22.

Measured Values
   ABP 501   Adalimumab 
Participants Analyzed 
[Units: Participants]
 264   262 
Percentage of Participants Who Developed Antibodies to ABP 501 or Adalimumab 
[Units: Percentage of participants]
   
Developing Binding Antibody   38.3   38.2 
Developing Neutralizing Antibody   9.1   11.1 

No statistical analysis provided for Percentage of Participants Who Developed Antibodies to ABP 501 or Adalimumab




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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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 agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


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