A Study of Mavrilimumab in Subjects With Moderate-to-Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of 3 subcutaneous doses of mavrilimumab compared with placebo in combination with methotrexate (MTX) in subjects with moderate-to-severe adult onset Rheumatoid Arthritis (RA).

Detailed Description
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Despite the therapeutic improvements with recent biologic agents approved for rheumatoid arthritis, there is still significant unmet medical need for the treatment of subjects with this chronic disease to achieve a faster, more complete response, and higher rates of remission. The aim of the study is to explore the optimum dose of mavrilimumab for further clinical development and more fully investigate the efficacy and safety profile of mavrilimumab after longer drug exposure (that is, 24 weeks). The results of this study will form the basis for future clinical studies with mavrilimumab.

Official Title
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A Phase 2b Study to Evaluate the Efficacy and Safety of Mavrilimumab in Subjects With Moderate-to-Severe Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Mavrilimumab 30 mg
* Biological: Mavrilimumab 100 mg
* Biological: Mavrilimumab 150 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of adult onset Rheumatoid Arthritis (RA) in line with the protocol Moderately active disease in line with the protocol A pre-defined number of swollen joints in line with the protocol Inadequate response to one or more conventional disease-modifying anti-rheumatic drugs (DMARDs) No evidence of respiratory disease. Exclusion Criteria: A rheumatic autoimmune disease other than RA, or significant systemic extra-articular involvement secondary to RA A history of, or current, inflammatory joint disease other than RA Previous treatment with the investigational drug Discontinuation of a biologic DMARD due to lack of efficacy Non-compliant concurrent medications Non-compliance with medical history criteria.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo matched to mavrilimumab (CAM-3001) injection subcutaneously every 2 weeks for 24 weeks in combination with stable dose of methotrexate (7.5 to 25 milligram [mg] per week) through oral or parenteral route. | Other: Placebo<br>* Placebo matched to mavrilimumab (CAM-3001) injection subcutaneously every 2 weeks for 24 weeks.<br>|
| Experimental: Mavrilimumab 30 mg<br>Mavrilimumab (CAM-3001) 30 mg injection subcutaneously every 2 weeks for 24 weeks in combination with stable dose of methotrexate (7.5 to 25 mg per week) through oral or parenteral route. | Biological: Mavrilimumab 30 mg<br>* Mavrilimumab (CAM-3001) 30 mg injection subcutaneously every 2 weeks for 24 weeks<br>* Other names: CAM-3001;|
| Experimental: Mavrilimumab 100 mg<br>Mavrilimumab (CAM-3001) 100 mg injection subcutaneously every 2 weeks for 24 weeks in combination with stable dose of methotrexate (7.5 to 25 mg per week) through oral or parenteral route. | Biological: Mavrilimumab 100 mg<br>* Mavrilimumab (CAM-3001) 100 mg injection subcutaneously every 2 weeks for 24 weeks.<br>* Other names: CAM-3001;|
| Experimental: Mavrilimumab 150 mg<br>Mavrilimumab (CAM-3001) 150 mg injection subcutaneously every 2 weeks for 24 weeks in combination with stable dose of methotrexate (7.5 to 25 mg per week) through oral or parenteral route. | Biological: Mavrilimumab 150 mg<br>* Mavrilimumab (CAM-3001) 150 mg injection subcutaneously every 2 weeks for 24 weeks.<br>* Other names: CAM-3001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score of 28 Joints Using C-Reactive Protein (DAS28 [CRP]) Score at Day 85 | DAS28 (CRP) calculated swollen joint count (SJC) and tender joint count (TJC) using the 28 joints, general health (GH) using participant assessment of disease activity (participant rated arthritis activity using the numerical rating scale with 0 = best, 10 = worst), and CRP (milligram per liter [mg/L]). Total score range: 0-9.4, higher score= more disease activity. DAS28 (CRP) less than (<) 3.2 = low disease activity, greater than or equal to (>=) 3.2 to 5.1 = moderate to high disease activity and <2.6= remission. A Day 85 responder was defined as a participant who experienced more than 1.2 decrease from baseline in DAS28 (CRP) score at Day 85. | Baseline and Day 85 | 
| Percentage of Participants Who Achieved American College of Rheumatology 20 (ACR20) Responses at Day 169 | ACR20 was defined as >=20 percent (%) improvement, in: SJC and TJC and >=20% 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 CRP. | Day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and Day 169 that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to Day 169 | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Treatment-Emergent Adverse Events (TEAEs) | Any medically significant change in laboratory evaluations were recorded as adverse events. Following parameters were analyzed for laboratory examination: hematology (haemoglobin, absolute neutrophil count, leukocyte count, platelet count), serum chemistry (alanine transaminase, aspartate transaminase, bilirubin, gamma-glutamyl transferase), other serum chemistry (low-density lipoprotein cholesterol, triglycerides), and urinalysis. | Baseline up to Day 169 | 
| Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs) | Vital sign assessments included blood pressure, pulse rate, temperature, weight and respiration rate. Vital signs abnormalities reported as TEAEs were reported. | Baseline up to Day 169 | 
| Percentage of Pulmonary Function Test Values Below Threshold Values at Day 169 | Pulmonary function testing were performed by spirometry to assess forced expiratory volume in 1 second (FEV1), forced expiratory volume in 6 second (FEV6), and forced vital capacity (FVC). FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. FEV6 was the maximal volume of air exhaled in the six second of a forced expiration from a position of full inspiration. FVC was the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. The percentage of predicted values of these pulmonary function tests were calculated based on decreases from baseline and categorized as less than or equal to (=<) 15 percent (%), more than (>) 15 to =<20%, and >20%. | Day 169 | 
| Dyspnea Score at Day 169 | Borg dyspnea scale is a validated participant reported outcome assessing participant's perceived difficulty in breathing (dyspnea). The scale ranges from 0 (nothing at all) to 10 (maximal difficulty). Higher scores indicate greater difficulty in breathing. | Day 169 | 
| Oxygen Saturation Level at Day 169 | Oxygen saturation measured by pulse oximetry which measures the concentration of oxygen in the blood. | Day 169 | 
| Percentage of Participants Who Achieved American College of Rheumatology 50 (ACR50) Responses at Day 169 | ACR50 was defined as >=50% improvement, in: SJC and TJC and >=50% 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 HAQ); and CRP. | Day 169 | 
| Percentage of Participants Who Achieved American College of Rheumatology 70 (ACR70) Responses at Day 169 | ACR70 was defined as >=70% improvement, in: SJC and TJC and >=70% 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 HAQ); and CRP. | Day 169 | 
| Change From Baseline in Continuous American College of Rheumatology (ACRn) Score at Day 169 | ACR score - continuous (ACRn) was defined as the minimum of the percentage improvement in TJC, SJC and the median of the percentage improvements in the other five components of the ACR criteria (participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; disability index of the HAQ; and CRP). Total score range was -100 to 100, where negative numbers indicated worsening and positive numbers indicated improvement. | Baseline up to Day 169 | 
| Percentage of Participants Who Achieved DAS28 (CRP) Response by European League Against Rheumatism (EULAR) Category at Day 169 | DAS28 (CRP) response by EULAR category were used to measure individual response as none, moderate, and good, depending on the extent of change from baseline and the level of disease activity reached. Good response: change from baseline >1.2 with baseline DAS28 (CRP) <3.2; moderate response: change from baseline >1.2 with baseline DAS28 (CRP) >=3.2 to less than or equal to (=<) 5.1 or change from baseline >=0.6 to =< 1.2 with baseline DAS28 (CRP) >=3.2 to =<5.1; no response: change from baseline <0.6 or change from baseline >=0.6 and =<1.2 with baseline DAS28 (CRP) >5.1. | Day 169 | 
| Percentage of Participants With DAS28 (CRP) Remission and Low Disease Activity at Day 169 | DAS28 (CRP) calculated SJC and TJC using the 28 joints, GH using participant assessment of disease activity (participant rated arthritis activity using the numerical rating scale with 0 = best, 10 = worst), and CRP (mg/L). Total score range: 0-9.4, higher score= more disease activity. Remission was defined as less than 2.6 DAS28 (CRP) score. Low disease activity was defined as less than 3.2 DAS28 (CRP) score. | Day 169 | 
| Mean Change From Baseline in Swollen and Tender Joint Count at Day 169 | Number of swollen joints was determined by examination of 66 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form, no swelling = 0, swelling =1. Number of tender joints was determined by examining 68 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form, no tenderness = 0, tenderness = 1. | Baseline and Day 169 | 
| Mean Change From Baseline in Patient Assessment of Pain at Day 169 | Participants rated the severity of arthritis pain on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS), where 0 mm = no pain and 100 mm = most severe pain. | Baseline and Day 169 | 
| Mean Change From Baseline in Patient Global Assessment (PGA) of Disease Activity at Day 169 | Participants responded to a question, Considering all the ways your arthritis affects you, how are you feeling today? by using a 0 - 100 millimeter (mm) VAS, where 0 = very well and 100 = very poorly. | Baseline and Day 169 | 
| Mean Change From Baseline in Physician Global Assessment of Disease Activity (MDGA) at Day 169 | Physician Global Assessment of Arthritis was measured by asking the physician to assess the participant's current arthritis disease activity by placing a vertical line on a 0 to 10 centimeter (cm) VAS, where 0 cm = very good and 10 cm = very bad. | Baseline and Day 169 | 
| Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Day 169 | 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 was 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 from 0 to 3; where 0 = least difficulty and 3 = extreme difficulty. | Baseline and Day 169 | 
| Ratio of Change From Baseline in C-Reactive Protein (CRP) at Day 169 | CRP is a substance produced by the liver that increases in the presence of inflammation in the body. 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 in underlying disease. | Baseline, Day 169 | 
| Ratio of Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Day 169 | 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. The farther the red blood cells have descended, the greater the inflammatory response. | Baseline, Day 169 | 
| Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission at Day 169 | The SDAI was the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, patient global assessment and physician global assessment assessed on 0 - 10 cm VAS; and C-reactive protein (CRP) (milligram per deciliter [mg/dL]). The SDAI total score ranges from 0 to 86, where higher scores indicates greater affection due to disease activity. SDAI remission was defined as a score less than or equal to 3.3. | Day 169 | 
| Percentage of Participants With Clinical Disease Activity Index (CDAI) Remission at Day 169 | The CDAI was the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, patient global assessment and physician global assessment assessed on 0 - 10 cm VAS. The CDAI total score ranges from 0 to 76 where higher scores indicates greater affection due to disease activity. CDAI remission was defined as a score less than or equal to 2.8. | Day 169 | 
| Percentage of Participants With American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Remission at Day 169 | ACR/EULAR remission was defined as swollen joint count (0-66), tender joint count (0-68), CRP (mg/dL) and participant global assessment (0-10) all less than or equal to one. | Day 169 | 
| Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-fatigue) at Day 169 | FACIT-F is a 13-item questionnaire questionnaire to measure the degree of fatigue experiences by participants in the previous 7 days. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). Larger the participant's response to the questions (with the exception of 2 negatively stated), greater was the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score) where higher sore represent less fatigue. | Baseline and Day 169 | 
| Serum Concentrations of Mavrilimumab | Serum concentrations after multiple subcutaneous doses of mavrilimumab were calculated for each cohort (30mg, 100mg and 150mg). Geometric coefficient of variation at Baseline for cohorts 30mg and 150mg were calculated as the negligible mean value was observed. | Baseline, Day 8, 15, 29, 85, 141, and 169 | 
| Percentage of Participants Exhibiting Anti-Drug Antibodies (ADAs) to Mavrilimumab at Any Visit | Immunogenicity assessment included determination of anti-drug (mavrilimumab) antibodies in serum samples. ADA detection measured by using electrochemiluminescence assays. | Day 1 to Day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, Mavrilimumab, CAM-3001