MSB11022 in Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy, safety and immunogenicity of MSB11022 and Humira® in adult participants with rheumatoid arthritis (RA).

Official Title
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A Multicenter, Randomized, Double-blind, Phase III Trial to Evaluate the Safety, Immunogenicity, and Efficacy of MSB11022 Compared With Humira® in Patients With Moderately to Severely Active Rheumatoid Arthritis

Conditions
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Moderate to Severe Rheumatoid Arthritis

Intervention / Treatment
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* Drug: MSB11022
* Drug: EU-Humira


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of rheumatoid arthritis based on 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria At least 6 tender (of 68 assessed) and 6 swollen (of 66 assessed) joints at screening and baseline Must have received methotrexate for at least 12 weeks and been on a stable dose for at least 4 weeks prior to the first study dose Other protocol defined inclusion criteria could apply Exclusion Criteria: Evidence of untreated or inadequately treated latent or active Tuberculosis Evidence of uncontrolled, clinically significant diseases Any second disease-modifying antirheumatic drugs must be washed out prior to the first study dose Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSB11022<br> | Drug: MSB11022<br>* Participants received MSB11022 (modified buffer and stabilizer) subcutaneously at dose of 40 milligram (mg) every other week from Day 1 up to Week 48.<br>* Other names: Adalimumab;|
| Active Comparator: EU-Humira<br> | Drug: EU-Humira<br>* Participants received EU-Humira subcutaneously at dose of 40 mg every other week from Day 1 up to Week 48.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-emergent Adverse Events of Special Interest (AESI) | Adverse event (AE) was defined as any untoward medical occurrence in participants, which does not necessarily have causal relationship with treatment. Term Treatment-emergent Adverse Events (TEAE) is defined as AEs starting/worsening after first intake of the study drug. Hypersensitivity was the pre-defined TEAE of special Interest for this study. The percentage of participants with treatment emergent AESIs (hypersensitivity) were reported. | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved American College of Rheumatology 20 (ACR20) Response at Week 12 | The ACR 20 Response is defined as greater than or equal to (>=) 20 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >=20 percent improvement in 3 of following 5 assessments: participant's assessment of pain using Visual Analog Scale (VAS ; 0-10 millimeter [mm], 0 mm=no pain and 10 mm=worst possible pain), participant's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI, defined as a 20-question instrument assessing 8 functional areas). The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and acute-phase marker (CRP). | Week 12 | 
| Percentage of Participants With Positive Anti-Drug Antibodies (ADAs) Status to Adalimumab | Percentage of participants with positive anti-Drug antibodies (ADAs) status to Adalimumab were reported. | Baseline, Week 2, 4, 12, 24, 36 and 52 | 
| Anti-Drug Antibodies (ADAs) Titer Levels for Adalimumab | Titer was defined as the degree to which the antibody-serum sample could be diluted and still contained detectable amounts of antibody. Anti-Drug Antibodies (ADAs) titers for adalimumab was reported. Data was collected using validated bioanalytical method. | Baseline, Week 2, 4, 12, 24, 36 and 52 | 
| Percentage of Participants With Confirmed Neutralizing Antibodies (NAb) Status to Adalimumab | Percentage of participants with confirmed neutralizing antibodies status to Adalimumab were reported. | Baseline, Week 2, 4, 12, 24, 36 and 52 | 
| Percentage of Participants Who Achieved American College of Rheumatology 20 (ACR20) Response at Week 2, 4, 8, 24 and 52 | The ACR 20 Response is defined as greater than or equal to (>=) 20 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >=20 percent improvement in 3 of following 5 assessments: patient's assessment of pain using Visual Analog Scale (VAS ; 0-10 millimeter [mm], 0 mm=no pain and 10 mm=worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI, defined as a 20-question instrument assessing 8 functional areas). The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and acute-phase marker (CRP). | Week 2, 4, 8, 24 and 52 | 
| Percentage of Participants Who Achieved American College of Rheumatology 50 (ACR50) Response at Week 2, 4, 8, 12, 24 and 52 | The ACR 50 Response is defined as greater than or equal to (>=) 50 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >=50 percent improvement in 3 of following 5 assessments: patient's assessment of pain using Visual Analog Scale (VAS ; 0-10 millimeter [mm], 0 mm=no pain and 10 mm=worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI, defined as a 20-question instrument assessing 8 functional areas). The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and acute-phase marker (CRP). | Week 2, 4, 8, 12, 24 and 52 | 
| Percentage of Participants Who Achieved American College of Rheumatology 70 (ACR70) Response at Week 2, 4, 8, 12, 24 and 52 | The ACR 70 Response is defined as greater than or equal to (>=) 70 percent improvement in swollen joint count (66 joints) and tender joint count (68 joints) and >=70 percent improvement in 3 of following 5 assessments: patient's assessment of pain using Visual Analog Scale (VAS ; 0-10 millimeter [mm], 0 mm=no pain and 10 mm=worst possible pain), patient's global assessment of disease activity by using VAS (the scale ranges from 0 mm to 100 mm, [0 mm=no pain to 100 mm=worst possible pain]), physician's global assessment of disease activity using VAS, participant's assessment of physical function measured by Health Assessment Questionnaire-Disability Index (HAQ-DI, defined as a 20-question instrument assessing 8 functional areas). The derived HAQ-DI ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and acute-phase marker (CRP). | Week 2, 4, 8, 12, 24 and 52 | 
| Change From Baseline in Disease Activity Score Based on a 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Week 2, 4, 8, 12, 24 and 52 | DAS calculated on 28 joints is composite score derived from 4 measures: number of swollen joints (out of 28), number of tender joints (out of 28), Erythrocyte sedimentation rate (ESR), Patient's Global Assessment of Disease Activity on visual analog scale (VAS). Overall disease activity score DAS28 was derived using following formulas from DAS28:DAS28=0.56*√(TJC28)+0.28*√(SJC28) + 0.014*GH+0.70*ln(ESR). Where: TJC28 = 28 joint count for tenderness, SJC28 = 28 joint count for swelling, ln(ESR) = natural log of ESR, GH = general health component of DAS (ie, Patient's Global Assessment of Disease Activity, assessed using scale of 1-100 where 100 is maximal activity); For analyses, GH divided by 10 & converted to 0.5 scale, i.e, 0, 0.5, 1, 1.5. DAS28-ESR of >5.1 implies active disease, <3.2 low disease activity, & <2.6 remission. Change of 1.2(twice measurement error)=significant change of disease activity state. Overall score ranges from 0-10 where higher score means more severe disease. | Baseline, Week 2, 4, 8, 12, 24 and 52 | 
| Percentage of Participants With Disease Activity Score Based on 28-joints Count- Erythrocyte Sedimentation Rate (DAS28-ESR) Low Disease Activity and Remission at Week 2, 4, 8, 12, 24, and 52 | Disease Activity Score calculated on 28 joints is composite score derived from 4 measures: number of swollen joints (out of 28), -number of tender joints (out of 28), -Erythrocyte sedimentation rate (ESR), -Patient's Global Assessment of Disease Activity on visual analog scale (VAS). Overall disease activity score DAS28 was derived using following formulas from DAS28: DAS28=0.56*√(TJC28)+0.28*√(SJC28) + 0.014*GH+0.70*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 DAS (ie, Patient's Global Assessment of Disease Activity, assessed using scale of 1 to 100 where 100 is maximal activity); For analyses, GH was divided by 10 and converted to a 0.5 scale, i.e., 0, 0.5, 1, 1.5. DAS28-ESR of >5.1 implies active disease, <3.2 low disease activity, and <2.6 remission. | Week 2, 4, 8, 12, 24, and 52 | 
| Change From Baseline in Simplified Disease Activity Index (SDAI) Total Score at Week 2, 4, 8, 12, 24, and 52 | SDAI is numerical sum of 5 outcome parameters: tender & swollen joint count (based on 28-joint assessment), Patient's & Physician's Global Assessment of Disease Activity (VAS) & level of C-reactive protein (CRP)(milligram per deciliter (mg/dL), normal<1 mg/dL). SDAI was calculated based on following formula: SDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28)+GH+PGA+CRP Where: -GH =general health component of DAS (i.e. Patient's Global Assessment of Disease Activity, assessed using scale of 1 to 100 where 100 is maximal activity; For analyses, GH was divided by 10 & converted to 0.5 scale (0, 0.5, 1, 1.5).-PGA = Physician's Global Assessment of Disease Activity assessed using scale of 1 to 100 where 100 is maximal activity. For analyses, PGA will be divided by 10 & converted to 0.5 scale (0, 0.5, 1, 1.5). where [0-0.25] = 0, [0.25-0.75] = 0.5, [0.76-1.25] = 1, etc. The total score range is 0-86 & lower score indicates less disease activity. | Baseline, Week 2, 4, 8, 12, 24, and 52 | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) Total Score at Week 2, 4, 8, 12, 24 and 52 | Clinical Disease Activity Index (CDAI) is a composite index (without acute-phase reactant) for assessing disease activity. The CDAI was calculated based on following formula: CDAI = 28 joint count for swelling (SJC28) + 28 joint count for tenderness (TJC28) + GH + PGA. Where, -GH = general health component of the DAS (i.e., Patient's Global Assessment of Disease Activity, assessed using a scale of 1 to 100 where 100 is maximal activity; for analyses, GH was divided by 10 and converted to a 0.5 scale, i.e., 0, 0.5, 1, 1.5 etc. where [0-0.25] = 0, [0.25-0.75] = 0.5, [0.76-1.25] = 1, etc.). -PGA = Physician's Global Assessment of Disease Activity assessed using a scale of 1 to 100 where 100 is maximal activity. For analyses, PGA was divided by 10 and converted to a 0.5 scale, ie, 0, 0.5, 1, 1.5 etc. where [0-0.25] = 0, [0.25-0.75] = 0.5, [0.76-1.25] = 1, etc. The CDAI ranges from 0 to 76. Lower score indicates less disease activity. | Baseline, Week 2, 4, 8, 12, 24 and 52 | 
| Percentage of Participants With American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean Remission at Week 2, 4, 8, 12, 24 and 52 | According to Boolean-based definition of remission of ACR/EULAR, a participant must satisfy all of the following: tender joint count <= 1, swollen joint count <= 1, CRP <= 1 mg/dL, and Patient's Global Assessment of Disease Activity <= 1 (0 to 10 VAS). PGA was assessed on a 10 mm VAS ranging from 0 (very well) to 10 (very poor), where higher scores indicate worse health condition. | Week 2, 4, 8, 12, 24 and 52 | 
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Leading to Death | Adverse event(AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. All abnormal physical examinations occurring during the study have been reported as Adverse events. TEAEs included both Serious TEAEs and non-serious TEAEs. | Baseline up to Week 69 | 
| Percentage of Participants With Clinically Meaningful Differences in Vital Signs | Vital signs including body temperature, respiratory rate, and heart rate (after 5-minute rest) were measured. Percentage of participants with clinically meaningful abnormalities in vital signs were reported. Clinical meaningful was determined by the investigator. | Up to Week 52 | 
| Percentage of Participants With Clinically Meaningful Differences in Laboratory Values | Laboratory parameters including hematology, urinalysis, and biochemistry analysis were analyzed. | Up to Week 52 | 
| Percentage of Participants With Clinically Significant Abnormal Values for 12-lead Electrocardiogram (ECG) at Week 12, 24, and 52 | Percentage of participants with clinically significant abnormal values for 12-lead electrocardiogram (ECG) at week 12, 24, and 52 were reported. | Week 12, 24, and 52 | 
| Percentage of Participants With Anti-Nuclear Antibody (ANA) and Anti Double-stranded Deoxyribonucleic Acid (Anti-dsDNA) at Baseline, Week 24 and 52 | For ANA, positivity is defined as any participant with ANA titer greater than (>) 1:160 and negativity is defined as ANA titer less than (<) 1:160. For anti-ds DNA, positivity is defined as any participant with adsDNA > 15 units per milliliter (U/mL), intermediate category is defined as value between 10 U/mL to 15 U/mL and negativity is defined as adsDNA < 10 U/mL. Percentage of participants with anti-nuclear antibody (ANA) and anti double-stranded deoxyribonucleic acid (Anti-dsDNA) at baseline, week 24 and 52 were reported. | Baseline, Week 24 and 52 | 
| Health Assessment Questionnaire Disability Index (HAQ-DI) Total Score at Baseline, Weeks 12, 24 and 52 | The HAQ-DI is a participant-reported questionnaire that is commonly used in RA to measure disease associated disability (assessment of physical function). It consists of several questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. HAQ-DI scores range from 0 to 3. The disability section of the questionnaire scores the participant's self-perception on the degree of difficulty (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do). | Baseline, Weeks 12, 24 and 52 | 
| Short-Form Health Survey- 36 Items (SF-36) at Baseline, Week 12, 24 and 52 | The Short Form Health Survey (SF-36) is a validated 36-item, patient-reported indication of overall health status not specific to any age, disease or Treatment group. The SF-36 questionnaire contains 36 questions pertaining to eight subscales of health status. These eight subscales were summarized as relating to either physical health or mental health. Physical component summary (PCS) is based primarily on physical functioning, role-physical, bodily pain, and general health scales and mental component summary (MCS) encompasses vitality, social functioning, role-emotional, and mental health scales. Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0-100 (100=highest level of mental functioning). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0-100 (100=highest level of physical functioning). | Baseline, Week 12, 24 and 52 | 
| Euro-Quality of Life - 5 Dimension-5 Levels (EQ-5D-5L) Utility Index Score at Baseline, Week 12, 24 and 52 | EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L descriptive system provides a profile of the participant's health state 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The participant was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. Responses to the 5 dimension scores were combined and converted into a single preference-weighted health utility index score 0 (0.0- worst health state) to 1 (1.0- better health state) representing the general health status of the individual based on the UK scoring algorithm. | Baseline, Week 12, 24 and 52 | 
| Euro-Quality of Life - 5 Dimension-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) Score at Baseline, Week 12, 24 and 52 | EQ-5D-5L: Standardized, participant-rated questionnaire to assess health-related quality of life. EQ-5D-5L includes 2 components: EQ-5D-5L health state profile (descriptive system) and EQ-5D-5L Visual Analog Scale. EQ-5D-5L descriptive system provides a profile of participant's health state 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. Responses to 5 dimension scores were combined and converted into single preference-weighted health utility index score 0 (worst health state) to 1 (better health state). EQ-VAS: Self-rated health status using a vertical VAS. EQ-VAS records participant's perceptions of their own current overall health in range from 0 (worst imaginable health) to 100 (best imaginable health). | Baseline, Week 12, 24 and 52 | 
| Mean Change From Baseline (Week 4) in Injection Site Pain as Assessed by Visual Analogue Scale (VAS) at Week 6 and 8 | The participant's reported perception of pain was measured on a VAS where the slash drawn by the participant represents pain of increasing intensity. VAS score ranges from 0-10 millimeter [mm], where; 0 mm=no pain and 10 mm=worst possible pain. The first 2 injections was administered by qualified personnel. The next three doses of IMP (3-5) will be self-administered by the participant and injection site pain was assessed. Pain was recorded immediately after, 15 minutes after, and 1 hour after the injections received by the participants. | Immediately, 15 minutes and 1 hour post-injection on Baseline (Week 4), Week 6 and 8 |