A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Efficacy and Safety of CAM-3001 in Subjects With Rheumatoid Arthritis
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Rheumatoid Arthritis
- Sponsor
- MedImmune LLC
- Enrollment
- 516
- Locations
- 1
- Primary Endpoint
- Percentage of Participants Who Achieved Disease Activity Score of 28 Joints Using C-Reactive Protein (DAS28 [CRP]) Response at Day 85 by Region
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The primary objectives of this study is to assess the safety, tolerability and efficacy of multiple doses of the mavrilimumab (CAM-3001) administered subcutaneously in subjects with moderately active Rheumatoid Arthritis (RA).
Detailed Description
This is a Phase 2, randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the efficacy and safety of multiple doses of the mavrilimumab (CAM-3001) (10 milligram \[mg\], 30 mg, 50 mg, and 100 mg) administered subcutaneously in adult subjects with moderately active RA.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age 18 through 80 years (20 to 75 years in Japan)
- •Written consent
- •Diagnosis of adult onset Rheumatoid Arthritis (RA) of at least 3 months duration as defined by the 1987 American College of Rheumatology (ACR) classification criteria (Arnett et al, 1988)
- •Treatment with methotrexate at a stable and tolerated doses
- •Positive anti-cyclic citrullinated peptide (CCP) immuno-globulin G antibodies (more than \[\>\] 5 international unit per milliliter \[IU/mL\]) and/or rheumatoid factor (RF \>14 IU/mL) at screening
- •Received more than or equal to (\>=) 5 milligram (mg) per week folic acid as a single or divided dose during the study.
Exclusion Criteria
- •A rheumatic autoimmune disease other than RA
- •A history of, or current, inflammatory joint disease other than RA or other systemic autoimmune disorder
- •Subjects at a high risk of infection
- •Subjects (male and female) of reproductive potential who are not willing to use contraception from screening through the end date of the trial
- •History of methotrexate or any drug-induced lung fibrosis or pneumonitis.
Outcomes
Primary Outcomes
Percentage of Participants Who Achieved Disease Activity Score of 28 Joints Using C-Reactive Protein (DAS28 [CRP]) Response at Day 85 by Region
Time Frame: Day 85
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. DAS28 (CRP) \<3.2 = low disease activity, \>=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. DAS28 (CRP) response at Day 85 for the European and Japanese regions were reported.
Percentage of Participants Who Achieved Disease Activity Score of 28 Joints Using Erythrocyte Sedimentation Rate (DAS28 [ESR]) at Day 85 by Region
Time Frame: Day 85
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. A Day 85 responder was defined as a participant who experienced more than 1.2 decrease from baseline in DAS28 (ESR) score at Day 85. DAS28 (ESR) response at Day 85 for the European and Japanese regions were reported.
Percentage of Participants Who Achieved DAS28 (CRP) Response by European League Against Rheumatism (EULAR) Category at Day 85 by Region
Time Frame: Day 85
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 =\< 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. DAS28 (CRP) response by EULAR category at Day 85 for the European and Japanese regions were reported.
Percentage of Participants Who Achieved DAS28 (ESR) Response by European League Against Rheumatism (EULAR) Category at Day 85
Time Frame: Day 85
DAS28 (ESR) 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 (ESR) \<3.2; moderate response: change from baseline \>1.2 with baseline DAS28 (ESR) \>=3.2 to =\< 5.1 or change from baseline \>=0.6 to =\< 1.2 with baseline DAS28 (ESR) \>=3.2 to =\<5.1; no response: change from baseline \<0.6 or change from baseline \>=0.6 and =\<1.2 with baseline DAS28 (ESR) \>5.1.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Time Frame: Baseline up to Day 169 (follow-up)
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 up Day 169 that were absent before treatment or that worsened relative to pretreatment state.
Percentage of Participants Who Achieved Disease Activity Score of 28 Joints Using Erythrocyte Sedimentation Rate (DAS28 [ESR]) at Day 85
Time Frame: Day 85
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. A Day 85 responder was defined as a participant who experienced more than 1.2 decrease from baseline in DAS28 (ESR) score at Day 85.
Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at Day 85
Time Frame: Day 85
FEV1 was the maximal volume of air exhaled in the first 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.
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at Day 85
Time Frame: Baseline and Day 85
FEV1 was the maximal volume of air exhaled in the first 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.
Dyspnea Score at Day 85
Time Frame: Day 85
Modified 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.
Change From Baseline in Dyspnea Score at Day 85
Time Frame: Baseline and Day 85
Modified 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.
Oxygen Saturation Level at Day 85
Time Frame: Day 85
Oxygen saturation measured by pulse oximetry which measures the concentration of oxygen in the blood.
Percentage of Participants Who Achieved DAS28 (CRP) Response by European League Against Rheumatism (EULAR) Category at Day 85
Time Frame: Day 85
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 Abnormal Vital Signs Reported as Treatment-Emergent Adverse Events (TEAEs)
Time Frame: Baseline up to Day 169 (follow-up)
Vital sign assessments included blood pressure, pulse rate, temperature, and respiration rate. Vital signs abnormalities reported as TEAEs were reported.
Number of Participants With Abnormal Electrocardiogram (ECG) Results
Time Frame: Baseline up to Day 169 (follow-up)
12-lead ECG was recorded and corrected QT (QTc) interval was measured with the participant in a rested supine position for at least 10 minutes. Any ECG abnormality deemed clinically significant as per investigator's discretion were reported.
Diffusing Capacity for Carbon Monoxide (DLCO) at Day 85
Time Frame: Day 85
DLCO is a pulmonary function test that measures the partial pressure difference between inspired and expired carbon monoxide.
Diffusing Capacity for Carbon Monoxide (DLCO) at Day 85 by Region
Time Frame: Day 85
DLCO is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide. DLCO% for the European and Japanese regions were reported.
Change From Baseline in Diffusing Capacity for Carbon Monoxide (DLCO) at Day 85
Time Frame: Baseline and Day 85
DLCO is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide.
Categorized Dyspnea Score at Day 85
Time Frame: Day 85
Modified 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. The modified BORG dyspnea scale was categorized as - no/slight (0 to 2), moderate (3 and 4), severe (5 and 6) and very severe breathlessness (7 and above).
Percentage of Participants Who Achieved Disease Activity Score of 28 Joints Using C-Reactive Protein (DAS28 [CRP]) Response at Day 85
Time Frame: 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.
Oxygen Saturation Level at Day 85 by Region
Time Frame: Day 85
Oxygen saturation measured by pulse oximetry which measures the concentration of oxygen in the blood. Oxygen saturation for the European and Japanese regions were reported.
Change From Baseline in Oxygen Saturation Level at Day 85
Time Frame: Baseline and Day 85
Oxygen saturation measured by pulse oximetry which measures the concentration of oxygen in the blood.
Percentage of Participants Who Achieved DAS28 (ESR) Response by European League Against Rheumatism (EULAR) Category at Day 85 by Region
Time Frame: Day 85
DAS28 (ESR) 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 (ESR) \<3.2; moderate response: change from baseline \>1.2 with baseline DAS28 (ESR) \>=3.2 to =\< 5.1 or change from baseline \>=0.6 to =\< 1.2 with baseline DAS28 (ESR) \>=3.2 to =\<5.1; no response: change from baseline \<0.6 or change from baseline \>=0.6 and =\<1.2 with baseline DAS28 (ESR) \>5.1. DAS28 (ESR) response by EULAR category at Day 85 for the European and Japanese regions were reported.
Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) at Day 85 by Region
Time Frame: Day 85
FEV1 was the maximal volume of air exhaled in the first 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. FEV1 and FVC at Day 85 for the European and Japanese regions were reported.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Treatment-Emergent Adverse Events (TEAEs)
Time Frame: Baseline up to Day 169 (follow-up)
Any medically significant change in laboratory evaluations were recorded as adverse events. Following parameters were analyzed for laboratory examination: hematology (haemoglobin, reticulocytes, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes, mean corpuscular volume, mean corpuscular haemoglobin concentration); serum chemistry (creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, gamma glutamyl transferase, CRP, ESR, albumin, total cholesterol, triglycerides, rheumatoid factor and anti-cyclic citrullinated peptide antibodies); urinalysis (albumin, glucose, protein, blood, nitrite).
Secondary Outcomes
- Duration of DAS28 (CRP) and DAS28 (ESR) Response and Remission(Baseline up to Day 169)
- Continuous ACR (ACRn) Score(Day 85)
- Serum Concentration of C-Reactive Protein (CRP) by Region(Day 85)
- Change From Baseline in DAS28 (CRP) and DAS28 (ESR) at Day 85(Baseline and Day 85)
- Change From Baseline in DAS28 (CRP) and DAS28 (ESR) at Day 85 by Region(Baseline and Day 85)
- Percentage of Participants Who Achieved DAS28 (CRP) and DAS28 (ESR) Remission at Day 85(Day 85)
- Time to Onset for DAS28 (CRP) and DAS (ESR) Response and Remission(Baseline up to Day 169 (follow-up))
- Time to Onset for DAS28 (CRP) and DAS (ESR) Response and Remission by Region(Baseline up to Day 169 (follow-up))
- Continuous ACR (ACRn) Score by Region(Day 85)
- Swollen and Tender Joint Count(Day 85)
- Health Assessments Questionnaire-Disability Index (HAQ-DI) Score(Day 85)
- Percentage of Participants Who Achieved DAS28 (CRP) and DAS28 (ESR) Remission at Day 85 by Region(Day 85)
- Percentage of Participants Who Achieved American College of Rheumatology 20 (ACR20), ACR50 and ACR70 Responses at Day 85 by Region(Day 85)
- Number of Participants Who Achieved ACR Categorical Responses(Day 85)
- Health Assessments Questionnaire (HAQ) Pain Score(Day 85)
- Health Assessments Questionnaire (HAQ) Pain Score by Region(Day 85)
- Serum Concentration of C-Reactive Protein (CRP)(Day 85)
- Maximum Observed Serum Concentration (Cmax) for Mavrilimumab After First Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)
- Maximum Observed Serum Concentration (Cmax) for Mavrilimumab After Last Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Mavrilimumab After Last Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)
- Percentage of Participants Who Achieved American College of Rheumatology 20 (ACR20), ACR50 and ACR70 Responses at Day 85(Day 85)
- Physician Global Assessment of Disease Activity Score(Day 85)
- Physician Global Assessment of Disease Activity Score by Region(Day 85)
- Patient Global Assessment of Disease Activity Score(Day 85)
- Patient Global Assessment of Disease Activity Score by Region(Day 85)
- Serum Concentration of Erythrocyte Sedimentation Rate (ESR)(Day 85)
- Serum Concentration of Anti-Citrullinated-Peptide-Antibody (ACPA)(Day 85)
- Number of Participants With Change in Methotrexate (MTX) and Corticosteroid (CST) Dose(Baseline, Day 1 to 85, Day 86 to 169)
- Patient Pain Assessment Score(Day 85)
- Patient Pain Assessment Score by Region(Day 85)
- Number of Participants Exhibiting Anti-Drug Antibodies (ADAs) to Mavrilimumab at Any Visit(Day 1 up to Day 169)
- Swollen and Tender Joint Count by Region(Day 85)
- Health Assessments Questionnaire-Disability Index (HAQ-DI) Score by Region(Day 85)
- Serum Concentration of Erythrocyte Sedimentation Rate (ESR) by Region(Day 85)
- Number of Participants Who Had Additional Medications(Baseline up to Day 169)
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Mavrilimumab After First Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)
- Terminal Phase Elimination Half-Life (t1/2) for Mavrilimumab After Last Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)
- Serum Concentration of Rheumatoid Factor (RF)(Day 85)
- Time to Reach Maximum Observed Serum Concentration (Tmax) for Mavrilimumab After First Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)
- Time to Reach Maximum Observed Serum Concentration (Tmax) for Mavrilimumab After Last Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)
- Accumulation Ratio for Mavrilimumab After Last Dose by Region(Blood samples were collected at pre-dose on Days 1, 4, 8, 15, 29, 57, and 85 as well as during follow up on Days 88, 99, 113 and 169)