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BI 695501 Compared to Adalimumab in Patients With Active Rheumatoid Arthritis

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ClinicalTrials.gov Identifier: NCT02137226
Recruitment Status : Completed
First Posted : May 13, 2014
Results First Posted : December 8, 2017
Last Update Posted : January 19, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Arthritis, Rheumatoid
Interventions Drug: BI 695501
Drug: US-licensed Humira®
Enrollment 645
Recruitment Details A randomized, double-blind, parallel arm, multiple dose, active comparator trial to assess efficacy, safety and immunogenicity of BI 695501 versus adalimumab in patients with active rheumatoid arthritis. Patient received background methotrexate (MTX) treatment.
Pre-assignment Details One patient was initially treated with Humira and discontinued prior to Week 24. This patient was mistakenly re randomized to BI 695501 but not treated. For safety set this was counted in Humira not re-randomized group (as treated), and for other analysis sets, this patient was counted in the Humira to BI 695501 group (as randomized).
Arm/Group Title BI 695501 US-licensed Humira® BI 695501 to BI 695501 US-licensed Humira® to US-licensed Humira® US-licensed Humira® to BI 695501
Hide Arm/Group Description Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1). Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1). Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48. Patients initially randomized to US-licensed Humira® in Period 1 and re-randomized to US-licensed Humira® in Period 2. Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48. Patients initially randomized to US-licensed Humira® in Period 1 and re-randomized to BI 695501 in Period 2. Each patient received 40 mg/0.8 mL US-licenced Humira® in period 1 and 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.
Period Title: Period 1 (Initial Randomization)
Started 324 321 0 0 0
Completed 304 [1] 305 [1] 0 0 0
Not Completed 20 16 0 0 0
Reason Not Completed
Adverse Event             3             3             0             0             0
Withdrawal by Subject             11             5             0             0             0
Physician Decision             1             3             0             0             0
Lost to Follow-up             3             2             0             0             0
Lack of Efficacy             1             0             0             0             0
Other Reason             1             3             0             0             0
[1]
Not completed are discontinued from study
Period Title: Period 2 (Re - Randomization)
Started 0 0 298 148 147
Completed 0 0 281 [1] 140 [1] 138 [1]
Not Completed 0 0 17 8 9
Reason Not Completed
Adverse Event             0             0             3             1             4
Withdrawal by Subject             0             0             8             5             4
Physician Decision             0             0             0             1             0
Lost to Follow-up             0             0             3             0             0
Lack of Efficacy             0             0             2             0             0
Other Reason             0             0             1             1             1
[1]
Not completed are discontinued from study
Arm/Group Title BI 695501 US-licensed Humira® Total
Hide Arm/Group Description Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1). Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1). Total of all reporting groups
Overall Number of Baseline Participants 324 321 645
Hide Baseline Analysis Population Description
Safety Analysis Set (SAF): The SAF contained all patients who received at least one dose of trial drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 324 participants 321 participants 645 participants
53.7  (12.04) 53.6  (11.32) 53.6  (11.68)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 324 participants 321 participants 645 participants
Female
267
  82.4%
269
  83.8%
536
  83.1%
Male
57
  17.6%
52
  16.2%
109
  16.9%
1.Primary Outcome
Title The Proportion of Patients Meeting the American College of Rheumatology 20% (ACR20) Response Criteria at Week 12
Hide Description The proportion of patients meeting the ACR20 response criteria was assessed. A patient had an ACR20 response if all of the following occurred: A ≥ 20 % improvement in the swollen joint count (66 joints), A ≥ 20 % improvement in the tender joint count (68 joints), A ≥ 20 % improvement in at least three of the following assessments: Patient’s assessment of pain, Patient’s global assessment of disease activity (equivalent to the General Health component of the Disease Activity Score (DAS)), Physician’s global assessment of disease activity, Patient’s assessment of physical function, as measured by the Health Assessment Questionnaire – Disability Index (HAQ-DI) Acute phase reactant (C-reactive protein (CRP)).The Full Analysis Set contained all enrolled patients who were randomized to trial drug and who received at least one dose of trial drug and had all efficacy measures relevant for the co-primary efficacy endpoints measured at baseline and at least once post- baseline.
Time Frame Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set. Patients who discontinued treatment prior to the time-point had their binary response imputed as non-responder, a method commonly known as non-responder imputation. For truly missing data at the component level, multiple imputation was used.
Arm/Group Title BI 695501 US-licensed Humira®
Hide Arm/Group Description:
Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
Overall Number of Participants Analyzed 321 318
Measure Type: Number
Unit of Measure: Percentage of Patients
67.0 61.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira®
Comments The week 12 confidence interval for the estimated difference in proportion is produced using the cumulative distribution function method of Reeve
Type of Statistical Test Non-Inferiority or Equivalence
Comments The 90% Confidence Interval (CI) for ACR20 at Week 12, rounded to 1 decimal place, had to be entirely contained in the predefined equivalence region [-12.0%, 15.0%]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in proportions
Estimated Value 5.9
Confidence Interval (2-Sided) 90%
-0.9 to 12.7
Estimation Comments Results from logistic regression model adjusted for treatment, prior exposure to a biologic agent (yes / no), Baseline DAS28 (ESR). Difference in ACR20 Response Rate (BI695501 – Humira, %) is presented.
2.Primary Outcome
Title The Proportion of Patients Meeting ACR20 Response Criteria at Week 24
Hide Description ACR20 at Week 12 and Week 24 are standard outcome criteria that are widely accepted for regulatory purposes to demonstrate efficacy in treating the signs and symptoms of Rheumatoid arthritis (RA). The proportion of patients meeting the ACR20 response criteria was assessed at Week 12 and Week 24 to provide a robust comparison with US-licensed Humira® data. A patient had an ACR20 response if all of the following occurred: A ≥ 20 % improvement in the swollen joint count (66 joints), A ≥ 20 % improvement in the tender joint count (68 joints), A ≥ 20 % improvement in at least three of the following assessments: Patient’s assessment of pain, Patient’s global assessment of disease activity (equivalent to the General Health component of the Disease Activity Score ([DAS]), Physician’s global assessment of disease activity, Patient’s assessment of physical function, as measured by the Health Assessment Questionnaire – Disability Index (HAQ-DI) Acute phase reactant (C-reactive protein [CRP]).
Time Frame Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set. Patients who discontinued treatment prior to the time-point had their binary response imputed as non-responder, a method commonly known as non-responder imputation. For truly missing data at the component level, multiple imputation was used.
Arm/Group Title BI 695501 US-licensed Humira®
Hide Arm/Group Description:
Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
Overall Number of Participants Analyzed 321 318
Measure Type: Number
Unit of Measure: Percentage of Patients
69.0 64.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira®
Comments The week 24 confidence interval for the estimated difference in proportion is produced using the cumulative distribution function method of Reeve
Type of Statistical Test Non-Inferiority or Equivalence
Comments The 95% Confidence Interval (CI) for ACR20 at Week 24, rounded to 1 decimal place, had to be entirely contained in the predefined equivalence region [-15.0%;+15.0%]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in proportions
Estimated Value 4.5
Confidence Interval (2-Sided) 95%
-3.4 to 12.5
Estimation Comments Results from logistic regression model adjusted for treatment, prior exposure to a biologic agent (yes / no), Baseline DAS28 (ESR). Difference in ACR20 Response Rate (BI695501 – Humira, %) is presented.
3.Secondary Outcome
Title Change From Baseline in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 12 and Week 24
Hide Description

The DAS28 (ESR) score was derived using the following formulae:

DAS28 (ESR) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*(GH) + 0.7*ln(ESR)

Where:

  • TJC28 = 28 joint count for tenderness
  • SJC28 = 28 joint count for swelling
  • Ln (ESR) = natural logarithm of ESR
  • GH = General Health component of the DAS (patient’s global assessment of disease activity). DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. Actual number of patient analysed (N) is mean number of subjects in the analysis set with DAS28(ESR) results computable across the multiply imputed data sets. It is 319.6, 317.1 for week 12 and 313.9, 315.1 for week 24 for BI 695501 and US-licensed Humira® respectively.
Time Frame Baseline, Week 12 and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set. Patients who discontinued treatment prior to the time-point had their binary response imputed as non-responder, a method commonly known as non-responder imputation. For truly missing data at the component level, multiple imputation was used.
Arm/Group Title BI 695501 US-licensed Humira®
Hide Arm/Group Description:
Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
Overall Number of Participants Analyzed 321 318
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Units on a scale
Week 12
-2.1
(-2.28 to -2.01)
-2.0
(-2.18 to -1.91)
Week 24
-2.4
(-2.51 to -2.21)
-2.4
(-2.54 to -2.24)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira®
Comments Results based on DAS28 (ESR) mean changes from Baseline after 12 weeks of treatment = overall mean + treatment group + Baseline DAS28 (ESR) + prior exposure to a biologic agent + random error.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence margin is not applicable
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.1
Confidence Interval (2-Sided) 90%
-0.25 to 0.05
Estimation Comments Difference in least square means of BI 695501 – Humira is presented.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 695501, US-licensed Humira®
Comments Results based on DAS28 (ESR) mean changes from Baseline after 24 weeks of treatment = overall mean + treatment group + Baseline DAS28 (ESR) + prior exposure to a biologic agent + random error.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence margin is not applicable
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.17 to 0.23
Estimation Comments Difference in least square means of BI 695501 – Humira is presented.
4.Secondary Outcome
Title The Percentage of Patients With Investigator-assessed Drug-related Adverse Events (AEs) During the Treatment Phase
Hide Description The analysis of AEs was based on the concept of treatment-emergent AEs (TEAEs). Thus, all AEs with an onset after the first dose of trial drug up to a period of ten weeks after the last dose of trial drug were assigned to the current treatment for evaluation. Investigator-assessed drug related AEs were AEs with a relationship to drug ticked “yes” according to the Investigator. Overall results are presented from Day 1 up to Week 58 and are based on the initial randomization groups. The comparison therefore focuses on patients who received BI 695501 continuously versus patients who received Humira® continuously for the long term assessment of safety. One patient was initially treated with Humira and discontinued prior to Week 24. This patient was mistakenly re randomized to BI 695501 but not treated. For safety this was counted in Humira not re-randomized group (as treated), and for other analysis sets, this patient was counted in the Humira to BI 695501 group (as randomized).
Time Frame From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Analysis Set contained all patients who received at least one dose of trial drug.
Arm/Group Title BI 695501 Continuously US-licensed Humira® Continuously
Hide Arm/Group Description:
BI 695501 continuously comprised all patients randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 (or not re randomized at Week 24). This group represents all patients who were to receive BI 695501 from Day 1 to Week 48. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks.
Humira® US continuously comprised all patients randomized to US-licensed Humira® in Period 1 and re-randomized to US-licensed Humira® in Period 2 or not re randomized at Week 24 (e.g. patients who discontinued treatment prior to Week 24). This group represents all patients who were to receive US-licensed Humira® from Day 1 to Week 48. Each patient received 40 mg/0.8 mL US-licensed Humira® solution for injection, administered by SC injection every 2 weeks.
Overall Number of Participants Analyzed 324 175
Measure Type: Number
Unit of Measure: Percentage of Patients
19.1 22.9
Time Frame From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks
Adverse Event Reporting Description Treatment-emergent adverse events are defined as adverse events that started or worsened on or after the first dose of study medication and prior to the last date of study medication plus 10 weeks (70 days) inclusive. Data is reported from Day 1 to the end of Period 2 (Week 58).
 
Arm/Group Title BI 695501 Continuously US-licensed Humira® Continuously
Hide Arm/Group Description BI 695501 continuously comprised all patients randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 (or not re randomized at Week 24). This group represents all patients who were to receive BI 695501 from Day 1 to Week 48. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks. Humira® US continuously comprised all patients randomized to US-licensed Humira® in Period 1 and re-randomized to US-licensed Humira® in Period 2 or not re randomized at Week 24 (e.g. patients who discontinued treatment prior to Week 24). This group represents all patients who were to receive US-licensed Humira® from Day 1 to Week 48. Each patient received 40 mg/0.8 mL US-licensed Humira® solution for injection, administered by SC injection every 2 weeks.
All-Cause Mortality
BI 695501 Continuously US-licensed Humira® Continuously
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
BI 695501 Continuously US-licensed Humira® Continuously
Affected / at Risk (%) Affected / at Risk (%)
Total   18/324 (5.56%)   17/174 (9.77%) 
Cardiac disorders     
Atrial fibrillation  1  0/324 (0.00%)  1/174 (0.57%) 
Hypertensive cardiomyopathy  1  0/324 (0.00%)  1/174 (0.57%) 
Ventricular arrhythmia  1  0/324 (0.00%)  1/174 (0.57%) 
Eye disorders     
Macular degeneration  1  1/324 (0.31%)  0/174 (0.00%) 
Gastrointestinal disorders     
Chronic gastritis  1  0/324 (0.00%)  1/174 (0.57%) 
Gastrointestinal haemorrhage  1  1/324 (0.31%)  0/174 (0.00%) 
Intestinal obstruction  1  1/324 (0.31%)  0/174 (0.00%) 
General disorders     
Chest pain  1  1/324 (0.31%)  0/174 (0.00%) 
Immune system disorders     
Anaphylactic reaction  1  0/324 (0.00%)  1/174 (0.57%) 
Infections and infestations     
Appendicitis  1  0/324 (0.00%)  1/174 (0.57%) 
Arthritis infective  1  0/324 (0.00%)  1/174 (0.57%) 
Bronchitis  1  0/324 (0.00%)  1/174 (0.57%) 
Cellulitis  1  1/324 (0.31%)  0/174 (0.00%) 
Otitis media  1  1/324 (0.31%)  0/174 (0.00%) 
Pneumonia  1  0/324 (0.00%)  3/174 (1.72%) 
Pyelonephritis acute  1  0/324 (0.00%)  2/174 (1.15%) 
Injury, poisoning and procedural complications     
Craniocerebral injury  1  1/324 (0.31%)  0/174 (0.00%) 
Fall  1  0/324 (0.00%)  1/174 (0.57%) 
Femoral neck fracture  1  1/324 (0.31%)  0/174 (0.00%) 
Head injury  1  0/324 (0.00%)  1/174 (0.57%) 
Joint injury  1  0/324 (0.00%)  1/174 (0.57%) 
Lumbar vertebral fracture  1  1/324 (0.31%)  0/174 (0.00%) 
Rib fracture  1  1/324 (0.31%)  0/174 (0.00%) 
Road traffic accident  1  1/324 (0.31%)  0/174 (0.00%) 
Investigations     
Alanine aminotransferase increased  1  1/324 (0.31%)  0/174 (0.00%) 
Aspartate aminotransferase increased  1  1/324 (0.31%)  0/174 (0.00%) 
Hepatic enzyme increased  1  1/324 (0.31%)  0/174 (0.00%) 
Musculoskeletal and connective tissue disorders     
Intervertebral disc disorder  1  1/324 (0.31%)  0/174 (0.00%) 
Joint destruction  1  0/324 (0.00%)  1/174 (0.57%) 
Muscular weakness  1  1/324 (0.31%)  0/174 (0.00%) 
Rheumatoid arthritis  1  1/324 (0.31%)  0/174 (0.00%) 
Systemic lupus erythematosus  1  1/324 (0.31%)  0/174 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer  1  0/324 (0.00%)  1/174 (0.57%) 
Non-Hodgkin's lymphoma  1  0/324 (0.00%)  1/174 (0.57%) 
Prostatic adenoma  1  1/324 (0.31%)  0/174 (0.00%) 
Nervous system disorders     
Carotid artery stenosis  1  0/324 (0.00%)  1/174 (0.57%) 
Cerebrovascular accident  1  1/324 (0.31%)  0/174 (0.00%) 
Syncope  1  1/324 (0.31%)  0/174 (0.00%) 
Reproductive system and breast disorders     
Endometrial hyperplasia  1  1/324 (0.31%)  0/174 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Interstitial lung disease  1  1/324 (0.31%)  0/174 (0.00%) 
Vascular disorders     
Venous thrombosis limb  1  0/324 (0.00%)  1/174 (0.57%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
BI 695501 Continuously US-licensed Humira® Continuously
Affected / at Risk (%) Affected / at Risk (%)
Total   35/324 (10.80%)   24/174 (13.79%) 
Infections and infestations     
Nasopharyngitis  1  19/324 (5.86%)  17/174 (9.77%) 
Upper respiratory tract infection  1  17/324 (5.25%)  9/174 (5.17%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
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.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02137226     History of Changes
Other Study ID Numbers: 1297.2
2012-002945-40 ( EudraCT Number )
First Submitted: May 12, 2014
First Posted: May 13, 2014
Results First Submitted: September 11, 2017
Results First Posted: December 8, 2017
Last Update Posted: January 19, 2018