INCB028050 Compared to Background Therapy in Patients With Active Rheumatoid Arthritis (RA) With Inadequate Response to Disease Modifying Anti-Rheumatic Drugs

Study Overview
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Brief Summary
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This was a randomized, double blind, placebo controlled, dose ranging, parallel group study. Participants who had active rheumatoid arthritis (RA) who had inadequate response to any disease modifying anti-rheumatic drug (DMARD) therapy including biologics were enrolled. Screening evaluations were performed within approximately 28 days of randomization. The duration of the study was 6 months with the primary endpoint assessed at 3 months. Eligible participants were randomly assigned to one of three doses (4, 7 or 10 mg QD) of INCB028050 (Baricitinib) or placebo.

Official Title
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A Randomized, Double-blind, Placebo Controlled, Dose Ranging, Parallel Group, Phase 2 Study of INCB028050 Compared to Background Therapy in Patients With Active RA With Inadequate Response to Any Disease Modifying Anti-Rheumatic Drugs (DMARD) Therapy Including Biologics

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: INCB028050
* Drug: INCB028050
* Drug: INCB028050
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have rheumatoid arthritis which has been inadequately controlled with at least one DMARD For subjects receiving antimalarials, they must be treated with antimalarials for at least 6 months and receiving a stable daily dose For subjects receiving sulfasalazine, they must be treated with Sulfasalazine (SSZ) for at least 6 months and receiving a stable daily dose of no more than 3 grams per day For subjects on methotrexate, they must be treated with methotrexate for at least 6 months, and receiving a stable weekly dose of methotrexate between 7.5 and 25 mg For subjects on leflunomide, they must be treated with leflunomide for at least 6 months, and receiving a stable dose of leflunomide between 10 to 20 mg For subjects receiving corticosteroids, they must be on a dose not to exceed 10 mg of prednisone daily Active rheumatoid arthritis at the time of screening defined by the following: 6 or more joints tender or painful on motion and 4 or more swollen joints and at least one of the following two: Erythrocyte sedimentation rate (ESR) greater than or equal to 28 mm/hr or C-reactive protein (CRP) greater than or equal to 7 mg/liter Have evidence of lack of risk for tuberculosis Exclusion Criteria: Current or recent viral, bacterial, fungal, parasitic or mycobacterial infection requiring systemic therapy History of infected joint prosthesis Subjects who have a current or recent history of severe, progressive, uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological or cerebral disease Subjects who have received treatment with the following drugs or drug classes within the specified timeframe: prior treatment with rituximab within 12 months, prior treatment with an oral Janus kinase (JAK) inhibitor, DMARDs or other anti-rheumatic therapies not specified and allowed according to protocol, treatment with any investigational medication within 12 weeks or 5 half-lives (whichever is longer), and treatment with a biologic agent within 12 weeks prior to the first dose of study medication Subjects with a past history of neutropenia, thrombocytopenia or anemia requiring transfusion other than at the time of trauma or surgery, and subjects that meet protocol specified laboratory measures

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: INCB028050 4 mg QD<br>INCB028050 4mg Once daily (QD) | Drug: INCB028050<br>* 4 mg capsules QD<br>* Other names: Baricitinib;|
| Experimental: INCB028050 7 mg QD<br>INCB028050 7mg QD | Drug: INCB028050<br>* 7 mg capsules QD<br>* Other names: Baricitinib;|
| Experimental: INCB028050 10 mg QD<br>INCB028050 10mg QD | Drug: INCB028050<br>* 10 mg capsule QD<br>* Other names: Baricitinib;|
| Placebo Comparator: Placebo<br>Placebo group may 'cross-over' following 3 months of treatment to receive either active arm #2 (7mg QD) or active arm #3 (10mg QD) of INCB028050 capsules. | Drug: Placebo<br>* Placebo matching INCB028050 QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants Achieving American College of Rheumatology (ACR) 20 Improvement | The ACR 20 is defined as ≥ 20% improvement in tender joint count plus ≥ 20% improvement in swollen joint count plus ≥ 20% improvement in 3 of the following 5 criteria: participants' assessment of pain, participants' global assessment of disease activity (PGA), Physician's global assessment of disease activity (PHGA), participants' self-assessed disability Health Assessment Questionnaire (HAQ), and Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), whichever shows the greatest change. | Week 12 | 
| Participants With at Least 1 Adverse Event From Baseline Through Week 12 |  | From Baseline through week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With at Least 1 Adverse Event From Week 12 to Week 24 |  | Week 12 to Week 24 | 
| The Percentage of Participants Who Were Assigned to Active Treatment at Baseline Achieving ACR 20 Improvement at Week 24 | The ACR 20 is defined as ≥ 20% improvement in tender joint count plus ≥ 20% improvement in swollen joint count plus ≥ 20% improvement in 3 of the following 5 criteria: participants' assessment of pain, participants' global assessment of disease activity (PGA), Physician's global assessment of disease activity (PHGA), participants' self-assessed disability Health Assessment Questionnaire (HAQ), and Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), whichever shows the greatest change. | From Baseline to Week 24 | 
| The Percentage of Participants Achieving American College of Rheumatology (ACR) 50 Improvement at Week 12 and Week 24 | The ACR 50 is defined as ≥ 50% improvement in tender joint count plus ≥ 50% improvement in swollen joint count plus ≥50% improvement in 3 of the following 5 criteria: participants' assessment of pain, PGA, PHGA, participants' self-assessed disability HAQ, and ESR or CRP, whichever shows the greatest change. | Week 12 and Week 24 | 
| The Percentage of Participants Achieving American College of Rheumatology (ACR) 70 Improvement at Week 12 and Week 24 | The ACR 70 is defined as ≥ 70% improvement in tender joint count plus ≥ 70% improvement in swollen joint count plus ≥ 70% improvement in 3 of the following 5 criteria: participants' assessment of pain, PGA, PHGA, participants' self-assessed disability HAQ, and ESR or CRP, whichever shows the greatest change. | Week 12 and Week 24 | 
| The Percentage of Participants Achieving American College of Rheumatology (ACR) 90 Improvement at Week 12 and Week 24 | The ACR 90 is defined greater than or equal to (>=) 90 percent (%) improvement in painful and tender joint count; >= 90% improvement in swollen joint count; and >= 90% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP) at each visit. | Week 12 and Week 24 | 
| Change in Disease Activity Score 28 (DAS28) CRP Score From Baseline at Week 12 and Week 24 | Calculation of the disease activity score 28 (DAS 28) score was based on the tender joint count, plus swollen joint count, plus PGA, plus C-reactive protein (CRP). A higher score indicated more disease activity. The mean change from baseline (which represent decreases in the DAS 28 CRP scores) are shown as positive numbers in these analyses. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of the rheumatoid arthritis (>5.1=high disease activity; <3.2=low disease activity; <2.6=remission). | Baseline, Week 12 and Week 24 | 
| Change in Disease Activity Score 28 (DAS28) ESR Score From Baseline at Week 12 and Week 24 | Calculation of the disease activity score 28 (DAS 28) score was based on the tender joint count, plus swollen joint count, plus PGA, plus Erythrocyte sedimentation rate (ESR). The DAS28-ESR is expressed as units on a scale with the minimum score=0 (best) to maximum score=10 (worst). Remission was defined as DAS28-ESR <2.6. The mean change from baseline (which represent decreases in the DAS 28 ESR scores) are shown as positive numbers in these analyses. | Baseline, Week 12 and Week 24 | 
| Percentage of Participants Achieving Low Disease Activity by DAS28 (ESR)≤3.2 | Participants who achieved low disease activity based on the DAS 28 ESR (score ≤3.2). Participants who achieved low disease activity were classified as responders in this analysis. | Week 12 and Week 24 | 
| Percentage of Participants Achieving Remission by DAS28 (ESR) ≤2.6 | Participants who achieved inactive disease based on the DAS 28 ESR (score ≤2.6). Participants who achieved low disease activity were classified as responders in this analysis. | Week 12 and Week 24 | 
| Percentage of Participants Achieving Remission by DAS28 (CRP) ≤2.6 | Participants who achieved inactive disease based on DAS 28 CRP (score ≤2.6). Participants who achieved low disease activity were classified as responders in this analysis. | Week 12 and Week 24 | 
| Change in ACR Assessment Tender Joint Count (TJC) From Baseline to Week 12 and Week 24 | The 28 joints to be assessed for tenderness and swelling were shoulder, elbow, wrist, metacarpophalangeal (MCP) joints 1-5, proximal interphalangeal (PIP) joints 1-5, and knee on both sides of the body. The sum of tender joints ranged from 0 to 28 with 0 as best possible health status and 28 as worst health status. | Baseline, Week 12 and Week 24 | 
| Change in ACR Assessment Swollen Joint Count (SJC) From Baseline to Week 12 and Week 24 | The 28 joints to be assessed for tenderness and swelling were shoulder, elbow, wrist, metacarpophalangeal (MCP) joints 1-5, proximal interphalangeal (PIP) joints 1-5, and knee on both sides of the body. The sum of tender joints ranged from 0 to 28 with 0 as best possible health status and 28 as worst health status. | Baseline, Week 12 and Week 24 | 
| Change in Participants' Assessment of Pain From Baseline at Week 12 and Week 24 | Participants were to assess their current level of pain on a 100 mm horizontal Visual Analog Scale (VAS). The left-hand extreme of the line (0 mm) was described as no pain and the right-hand (100 mm) as most imaginable pain. | Baseline, Week 12 and Week 24 | 
| Change in Participants' Global Assessment of Disease Activity From Baseline at Week 12 and Week 24 | Participants were to assess the disease (RA) activity on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was described as no arthritis activity (symptom-free and no arthritis symptoms) and the right hand extreme (100 mm) as extremely active arthritis (maximum arthritis disease activity). A decreasing mean score, therefore, indicates improvement. | Baseline, Week 12 and Week 24 | 
| Change in Physician's Global Assessment of Disease Activity (PGA) From Baseline at Week 12 and Week 24 | Physicians were to assess the disease (RA) activity on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was described as no arthritis activity (symptom-free and no arthritis symptoms) and the right hand extreme (100 mm) as extremely active arthritis (maximum arthritis disease activity). A decreasing mean score, therefore, indicates improvement. | Baseline, Week 12 and Week 24 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline at Week 12 and Week 24 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. | Baseline, Week 12 and Week 24 | 
| Change in Erythrocyte Sedimentation Rate (ESR) From Baseline at Week 12 and Week 24 | ESR is a laboratory test that provides a non-specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 millimeter/hour (mm/hr). A higher rate is consistent with inflammation. | Baseline, Week 12 and Week 24 | 
| Change in C-reactive Protein (CRP) From Baseline at Week 12 and Week 24 | The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. | Baseline, Week 12 and Week 24 | 
| Change in Duration of Morning Stiffness From Baseline at Week 12 and Week 24 | Duration of morning stiffness was defined as the time elapsed when participant woke up in the morning and was able to resume normal activities without stiffness in minutes (If none was present = 0; If morning stiffness was continuing at the time of assessment or was unusual compared to the recent past, average of duration of stiffness over the past 3 days was reported; If stiffness persisted the entire day, 1440 minutes was recorded). | Baseline, Week 12 and Week 24 | 
| Percentage of Participants Achieving Good European League Against Rheumatism (EULAR) Response (DAS28 ESR) at Week 12 | EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. | Week 12 | 
| Percentage of Participants Achieving Good EULAR Response (DAS28ESR) at Week 24 | EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. | Week 24 | 
| Percentage of Participants Achieving Good EULAR Response (DAS28CRP) at Week 12 | EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 2.6. | Week 12 | 
| Percentage of Participants Achieving Good EULAR Response (DAS28CRP) at Week 24 | EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 2.6. | Week 24 | 
| Change in SF-36 Mental Component Summary From Baseline at Week 12 and Week 24 | The Health Assessment Questionnaire Short Form 36 (SF-36) determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Scales 5-8 primarily contribute to the mental component summary score (PCS) of the SF-36. Scores on each scale are summed and averaged (range = 0 worst-100 best). | Baseline, Week 12 and Week 24 | 
| Change in SF-36 Physical Component Summary From Baseline at Week 12 and Week 24 | The Health Assessment Questionnaire Short Form 36 (SF-36) determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Scales 1-4 primarily contribute to the physical component summary score (PCS) of the SF-36. Scores on each scale are summed and averaged (range = 0 worst-100 best). | Baseline, Week 12 and Week 24 | 
| Percent of Participants Achieving a Minimum Clinically Important Difference (MCID) in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 and Week 24 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. The MCID score for HAQ-DI is -0.22. | Week 12 and Week 24 | 
| Percent of Participants Achieving a MCID in the Pain Score (Participant's Assessment of Pain) at Week 12 and Week 24 | Participants were to assess their current level of pain on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was described as no pain and the right-hand (100 mm) as most imaginable pain. MCID for the pain score is a decrease of at least 10 mm on a 100 mm scale. | Week 12 and Week 24 | 
| Percent of Participants Achieving a MCID in the SF-36 Physical Components and Mental Components at Week 12 and Week 24 | The Health Assessment Questionnaire Short Form 36 (SF-36) determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Scales 5-8 primarily contribute to the mental component summary score (PCS) of the SF-36. Scores on each scale are summed and averaged (range = 0 worst-100 best). | Week 12 and Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis