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A Study of Mavrilimumab Versus Anti Tumor Necrosis Factor in Subjects With Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC
ClinicalTrials.gov Identifier:
NCT01715896
First received: October 16, 2012
Last updated: September 12, 2016
Last verified: September 2016
  Purpose
The primary objectives of this study is to explore the efficacy of mavrilimumab compared with golimumab in the treatment of adult subjects 18-80 years of age with moderate-to-severe active rheumatoid arthritis (RA) who have an inadequate response to one or more conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or one or two anti-tumor necrosis factor (TNF) agents (excluding golimumab) for efficacy or safety reasons.

Condition Intervention Phase
Rheumatoid Arthritis
Biological: Golimumab 50 mg
Biological: Mavrilimumab 100 mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2 Exploratory Study of Mavrilimumab Versus Anti-tumor Necrosis Factor in Subjects With Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by MedImmune LLC:

Primary Outcome Measures:
  • Percentage of Participants Who Achieved American College of Rheumatology 20 (ACR20) Responses at Day 169 [ Time Frame: Day 169 ]
    The ACR20 was defined as greater than or equal to (>=) 20 percent (%) improvement, in: swollen joint count (SJC) and tender joint count (TJC) and >=20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity (PGA); physician global assessment of disease activity (MDGA); self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-reactive protein (CRP). If CRP was missing and Erythrocyte sedimentation rate (ESR) was present then ESR was to be used.

  • Percentage of Participants Who Achieved American College of Rheumatology 50 (ACR50) Responses at Day 169 [ Time Frame: Day 169 ]
    The 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. If CRP was missing and ESR was present then ESR was to be used. The percentage of participants were calculated by logistic regression model method.

  • Percentage of Participants Who Achieved American College of Rheumatology 70 (ACR70) Responses at Day 169 [ Time Frame: Day 169 ]
    The 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. If CRP was missing and ESR was present then ESR was to be used. The percentage of participants were calculated by logistic regression model method.

  • Percentage of Participants Who Achieved Disease Activity Score of 28 Joints Using C-Reactive Protein (DAS28 [CRP]) Response at Day 169 [ Time Frame: Day 169 ]
    The DAS28 (CRP) was calculated from the number of SJC and TJC using the 28 joints count, The DAS28(CRP) considers 28 of the 68 TJC and 28 of the 66 SJC and participant's global health (GH) using PGA of disease activity using the visual analogue scale (VAS) of 0 (= best), 100 (= worst) plus levels of CRP (milligram/Liter [mg/L]). Total score range: 0-9.4, higher score= more disease activity. DAS28 (CRP) less than (<) 3.2 = low disease activity, >=3.2 to 5.1 = moderate to high disease activity and <2.6= remission. Participants with score less than 2.6 were analysed. The percentage of participants were calculated by logistic regression model method.

  • Percentage of Participants Who Achieved Health Assessment Questionnaire Disability Index (HAQ-DI) Score Improvement From Baseline and >= 0.25 at Day 169 [ Time Frame: Day 169 ]
    The HAQ-DI: 20-item scale assessing participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arising, eating, hygiene, walking, reaching, grip, and errands/chores 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. Participants with change from baseline more than or equal to (>=) 0.25 were reported. The percentage of participants were calculated by logistic regression model method.


Secondary Outcome Measures:
  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [ Time Frame: Baseline up to Day 169 ]
    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 pre-treatment state. TEAE and TESAE were reported as per relatedness and severity.

  • Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to Day 169 ]
    Any medically significant change in laboratory evaluations were recorded as adverse events. Following parameters were analyzed for laboratory examination: hematology (leukocytosis, neutropenia, anaemia of chronic disease); serum chemistry (alanine aminotransferase, blood parathyroid hormone, gamma glutamyl transferase, hepatic enzyme, dyslipidaemia, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hypertriglyceridaemia); urinalysis.

  • Number of Participants With Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline up to Day 169 ]
    Vital sign assessments included blood pressure, pulse rate, temperature, weight and respiration rate. Vital signs abnormalities reported as TEAEs were reported.

  • Number of Participants With Pulmonary Function Test Values Below Threshold Values Based on Percent Change From Baseline at Day 85 and 169 [ Time Frame: Day 85 and 169 ]
    Pulmonary function testing were performed by spirometry to assess forced expiratory volume in 1 second (FEV1), forced expiratory volume in 6 second (FEV6), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO). 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. DLCO is a pulmonary function test that measures the partial pressure difference between inspired and expired carbon monoxide. The percentage of predicted values of these pulmonary function tests were calculated based on decreases from baseline and categorized as more than (>) 20% reduction (RD) and absolute value (AV) less than (<) 80% predicted (PR).

  • Dyspnea Score at Day 169 [ Time Frame: Day 169 ]
    Borg dyspnea scale was 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 indicated greater difficulty in breathing.

  • Change From Baseline in Disease Activity Score of 28 Joints Using C-Reactive Protein (DAS28 [CRP]) Score at Day 169 [ Time Frame: Baseline and Day 169 ]
    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.

  • Change From Baseline in Continuous American College of Rheumatology (ACRn) Score at Day 169 [ Time Frame: Baseline up to 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. Mean indicates adjusted mean (Adj mean).

  • American College of Rheumatology (ACR) Hybrid Score at Day 169 [ Time Frame: Day 169 ]
    ACR Hybrid score 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.

  • Number of Participants Who Achieved DAS28 (CRP) Response by European League Against Rheumatism (EULAR) Category at Day 169 [ Time Frame: 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.

  • Number of Participants With DAS28 (CRP) Remission and Low Disease Activity at Day 169 [ Time Frame: 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.

  • Time to Onset DAS28 (CRP) Remission at Day 169 [ Time Frame: Day 169 ]
    The DAS28 (CRP) was calculated from the number of SJC and TJC using the 28 joints count, The DAS28(CRP) considers 28 of the 68 TJC and 28 of the 66 SJC and participant's global health (GH) using PGA of disease activity using the VAS of 0 (= best), 100 (= worst) plus levels of CRP (mg/L). Total score range: 0-9.4, higher score= more disease activity. DAS28 (CRP) <3.2 = low disease activity, >=3.2 to 5.1 = moderate to high disease activity and <2.6= remission. Participants with score less than 2.6 were analysed. Onset of DAS28(CRP) remission ≤ 2.6 defined as the first study day in which the DAS28 score met the criteria.

  • Duration of DAS28 (CRP) Remission at Day 169 [ Time Frame: Day 169 ]
    The DAS28 (CRP) was calculated from the number of SJC and TJC using the 28 joints count, The DAS28(CRP) considers 28 of the 68 TJC and 28 of the 66 SJC and participant's global health (GH) using PGA of disease activity using the VAS of 0 (= best), 100 (= worst) plus levels of CRP (mg/L). Total score range: 0-9.4, higher score= more disease activity. DAS28 (CRP) <3.2 = low disease activity, >=3.2 to 5.1 = moderate to high disease activity and <2.6= remission. Participants with score less than 2.6 were analysed. Duration of DAS28(CRP) remission for each subject was defined as number of days from onset of remission to when the subject was no longer in remission.

  • Percentage of Participants Who Achieved Disease Activity Score of 28 Joints Using Erythrocyte Sedimentation Rate (DAS28 [ESR]) < 2.6 at Day 169 [ Time Frame: Day 169 ]
    The DAS28 (ESR) 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 the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]). Total score range: 0-9.4, higher score = more disease activity. DAS28 (ESR) <3.2 = low disease activity, >=3.2 to 5.1 = moderate to high disease activity and <2.6= remission. The percentage of participants were calculated by logistic regression model method.

  • Percentage of Participants Who Achieved Simplified Disease Activity Index (SDAI) Remission at Day 169 [ Time Frame: 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 centimetre (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. The percentage of participants were calculated by logistic regression model method.

  • Percentage of Participants With Clinical Disease Activity Index (CDAI) Remission at Day 169 [ Time Frame: 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.

  • Percentage of Participants With American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Remission at Day 169 [ Time Frame: Day 169 ]
    The 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.

  • Mean Change From Baseline in Swollen and Tender Joint Count at Day 169 [ Time Frame: Baseline and 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. Mean here indicates adjusted mean.

  • Mean Change From Baseline in Patient Assessment of Pain at Day 169 [ Time Frame: Baseline and 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.

  • Mean Change From Baseline in Patient Global Assessment (PGA) of Disease Activity at Day 169 [ Time Frame: Baseline and 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 mm VAS, where 0 = very well and 100 = very poorly.

  • Mean Change From Baseline in Physician Global Assessment of Disease Activity (MDGA) at Day 169 [ Time Frame: Baseline and 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 cm VAS, where 0 cm = very good and 10 cm = very bad.

  • Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Day 169 [ Time Frame: Baseline and 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.

  • Ratio of Change C-Reactive Protein (CRP) at Day 169 to Baseline [ Time Frame: Baseline and Day 169 ]
    The ratio of change from baseline for CRP was analyzed and reported. The 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.

  • Erythrocyte Sedimentation Rate (ESR) at Day 169 [ Time Frame: 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.

  • Serum Concentrations of Mavrilimumab [ Time Frame: Baseline, Day 8, 15, 29, 85, 141, and 169 ]
    Serum concentrations after subcutaneous dose of mavrilimumab were calculated

  • Number of Participants Exhibiting Anti-Drug Antibodies (ADAs) to Mavrilimumab [ Time Frame: Day 1 to Day 169 ]
    Immunogenicity assessment included determination of anti-drug (mavrilimumab) antibodies in serum samples. ADA detection measured by using electrochemiluminescence assays.


Enrollment: 215
Study Start Date: March 2013
Study Completion Date: February 2015
Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Golimumab 50 mg alternating with Placebo
Participants received alternating doses of golimumab 50 milligram (mg) (Weeks 0, 4, 8, 12, 16, 20, and 24) and placebo matched to mavrilimumab (Weeks 2, 6, 10, 14, 18, and 22) injections 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: Golimumab 50 mg
Participants received alternating doses of golimumab 50 mg (Weeks 0, 4, 8, 12, 16, 20, and 24) and placebo matched to mavrilimumab (Weeks 2, 6, 10, 14, 18, and 22) injections 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.
Experimental: Mavrilimumab 100 mg
Participants received Mavrilimumab 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
Participants received Mavrilimumab 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.
Other Name: CAM-3001

Detailed Description:
Despite the therapeutic improvements with recent biologic agents approved for rheumatoid arthritis (RA), there is still a 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 current study is to compare the efficacy and safety of a subcutaneous dose of mavrilimumab with a marketed treatment for RA (golimumab) in 120 adult subjects with moderate-to-severe active RA who have had an inadequate response to one or two anti-TNF agents with mavrilimumab. The design of the study was exploratory and not formerly statistically powered.
  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 through 80 years
  • Written consent
  • Diagnosis of adult onset Rheumatoid Arthritis (RA) as defined by the 2010 American College of Rheumatology European League Against Rheumatism (ACR/EULAR) classification criteria
  • Moderately active disease as defined by disease activity score in 28 joints C-reactive protein (DAS28[CRP]) greater than or equal to (>=) 3.2 at screening and DAS28 erythrocyte sedimentation rate(ESR) ≥ 3.2 at Day 1
  • Inadequate response to one or more conventional disease-modifying anti-rheumatic drugs (DMARDs)
  • At least 4 swollen joints
  • Inadequate response to one or two anti-TNF agents other than the study comparator, as defined by the protocol
  • Receiving oral or injectable methotrexate, as defined by the protocol.

Exclusion Criteria:

  • A rheumatic autoimmune disease or other inflammatory joint disease other than RA
  • Previous treatment with biologic therapies other than anti-TNF for RA
  • Treatment with other DMARDs or non-steroidal anti-inflammatory drugs (NSAIDs), as defined by the protocol.
  • Medical history as defined by the protocol.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01715896

  Show 39 Study Locations
Sponsors and Collaborators
MedImmune LLC
Investigators
Study Director: Marius Albulescu MedImmune Ltd
  More Information

Responsible Party: MedImmune LLC
ClinicalTrials.gov Identifier: NCT01715896     History of Changes
Other Study ID Numbers: CD-IA-CAM-3001-1107
Study First Received: October 16, 2012
Results First Received: March 8, 2016
Last Updated: September 12, 2016

Keywords provided by MedImmune LLC:
Rheumatoid Arthritis
Golimumab
Mavrilimumab

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Necrosis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Methotrexate
Antibodies, Monoclonal
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on April 28, 2017