Efficacy, Safety and Tolerability of Denosumab in the Treatment of Rheumatoid Arthritis

Amgen227 enrolled

Overview

This study will determine the efficacy, safety, and tolerability of denosumab (AMG 162) in the treatment of Rheumatoid Arthritis (RA).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

227

Conditions

Rheumatoid Arthritis

Interventions

placeboDRUG

placebo subcutaneous injection

denosumabDRUG

For subcutaneous injection

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of RA. * All subjects will be required to have been taking a stable dose of methotrexate. * Active RA at screening defined as greater than or equal to 6 swollen joints. * The presence of erosive disease Exclusion Criteria: * Received any biologic agent (e.g., Enbrel®, Remicade®, Humira®, Kineret®) or Arava® within 8 weeks before randomization; past use of these agents is allowed. * Steroid use greater than 15 mg/day. * Scheduled for surgery or joint replacement in the hands, wrists or feet.

Outcomes

Primary Outcomes

Change From Baseline in Rheumatoid Arthritis Erosion Score Measured From MRI Assessments (RA-MRI ES) at Month 6

Fifteen sites in each wrist and 10 sites in each hand were assessed by a blinded and independent reader. Each site was scored from 0 to 10 (in accordance with the European League Against Rheumatism \[EULAR\]-Outcome Measures in Rheumatology Clinical Trials convention), with each unit increment representing 10% incremental loss of the peripheral 1 cm of articular bone. The Erosion Score is a sum of erosion scores from 50 joint sites in both hands/wrists and ranges from 0 (normal, no erosion) to 500 (worst possible erosion).

Time frame: Baseline, Month 6

Secondary Outcomes

Change From Baseline in Radiographic Total Modified Sharp Score (TSS) at Month 12

TSS is the sum of erosion and joint space narrowing scores obtained from radiographs of the hands and feet, assessed by 2 independent readers. The joint erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints in the feet. Each joint was scored, according to the surface area involved, from 0 (no erosion) to 5 (extensive loss of bone from more than one half of the articulating bone). Because each side of a foot joint was graded on this scale, the maximum erosion score for a foot joint was 10 and the maximal erosion score was 280. Joint Space Narrowing (JSN) Score summarizes the severity of JSN in 30 joints of the hands and 12 joints of the feet. Assessment of JSN for each hand (15 joints per hand) and foot (6 joints per foot), including subluxation, was scored from 0 (normal JSN) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score of 168. The TSS ranged from 0 (normal) to 448 (worst).

Time frame: Baseline, Month 12

Change From Baseline in Radiographic Total Modified Sharp Score (TSS) at Month 6

Data from ClinicalTrials.gov

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Time frame: Baseline, Month 6

Change From Baseline in Radiographic Erosion Score at Month 12

The joint erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints in the feet, obtained from radiographs of the hands and feet and assessed by 2 independent readers. Each joint was scored, according to the surface area involved, from 0 (no erosion) to 5 (extensive loss of bone from more than one half of the articulating bone). Because each side of a foot joint was graded on this scale, the maximum erosion score for a foot joint was 10 and the maximal erosion score was 280.

Time frame: Baseline, Month 12

Change From Baseline in Radiographic Erosion Score at Month 6

Time frame: Baseline, Month 6

Change From Baseline in Radiographic Joint Space Narrowing Score at Month 12

Joint Space Narrowing (JSN) Score summarizes the severity of JSN in 30 joints of the hands and 12 joints of the feet obtained from radiographs of the hands and feet and assessed by 2 independent readers. Assessment of JSN for each hand (15 joints per hand) and foot (6 joints per foot), including subluxation, was scored from 0 (normal JSN) to 4 (complete loss of joint space, bony ankylosis, or luxation), with a maximum JSN score (indicating worst joint space narrowing) of 168.

Time frame: Baseline, Month 12

Change From Baseline in Radiographic Joint Space Narrowing Score at Month 6

Time frame: Baseline, Month 6

Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 1

Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to Month 1 calculated using ((month 1 value - baseline value) / baseline value ) x 100. Least squares means are based on a repeated measures model adjusting for treatment, visit, baseline value, and strata (4 strata from the combination of baseline use of steroid and previous use of biologic).

Time frame: Baseline, Month 1

Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 6

Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to month 6 calculated using ((month 6 value - baseline value) / baseline value ) x 100. Least squares means are based on a repeated measures model adjusting for treatment, visit, baseline value, and strata (4 strata from the combination of baseline use of steroid and previous use of biologic).

Time frame: Baseline, month 6

Percent Change From Baseline in Lumbar Spine Bone Mineral Density at Month 12

Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to Month 12 calculated using ((Month 12 value - baseline value) / baseline value ) x 100. Least squares means based on repeated measures model adjusting for treatment, visit, baseline value, and strata (4 strata from the combination of baseline use of steroid and previous use of biologic).

Time frame: Baseline, Month 12

Percent Change From Baseline in Femoral Neck Bone Mineral Density at Month 1

Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to Month 1 calculated using ((Month 1 value - baseline value) / baseline value ) x 100. Least squares means based on repeated measures model adjusting for treatment, visit, baseline value, and strata (4 strata from the combination of baseline use of steroid and previous use of biologic).

Time frame: Baseline, Month 1

Percent Change From Baseline in Femoral Neck Bone Mineral Density at Month 6

Bone Mineral Density Assessed by Dual Energy X-Ray Absorptiometry. Percent change from baseline to Month 6 calculated using ((Month 6 value - baseline value) / baseline value ) x 100. Least squares means based on repeated measures model adjusting for treatment, visit, baseline value, and strata (4 strata from the combination of baseline use of steroid and previous use of biologic).

Time frame: Baseline, Month 6

Percent Change From Baseline in Femoral Neck Bone Mineral Density at Month 12

Time frame: Baseline, Month 12

Percent Change From Baseline in Total Hip Bone Mineral Density at Month 1

Time frame: Baseline, Month 1

Percent Change From Baseline in Total Hip Bone Mineral Density at Month 6

Time frame: Baseline, Month 6

Percent Change From Baseline in Total Hip Bone Mineral Density at Month 12

Time frame: Baseline, Month 12

Percent Change From Baseline in Serum Collagen C-Telopeptide (CTX) at Month 3

Percent change from baseline to Month 3 in serum Collagen C-Telopeptide (CTX) Type I calculated using ((Month 3 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 3

Percent Change From Baseline in Serum CTX at Month 6

Percent change from baseline to Month 6 in serum Collagen C-Telopeptide (CTX) Type I calculated using ((Month 6 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 6

Percent Change From Baseline in Serum CTX at Month 12

Percent change from Baseline to Month 12 in serum C-Telopeptide (CTX) Type I calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 12

Percent Change From Baseline in Procollagen 1 N-terminal Peptide (P1NP) at Month 3

Percent change from baseline to Month 3 in procollagen 1 N-terminal peptide (P1NP) calculated using ((Month 3 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 3

Percent Change From Baseline in P1NP at Month 6

Percent change from baseline to Month 6 in procollagen 1 N-terminal peptide (P1NP) calculated using ((Month 6 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 6

Percent Change From Baseline in P1NP at Month 12

Percent change from baseline to Month 12 in procollagen 1 N-terminal peptide (P1NP) calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 12

Percent Change From Baseline in Urine Type II Collagen C-telopeptide (C-Tx) /Creatinine at Month 3

Percent change from baseline to Month 3 in urine Type II collagen C-Telopeptide (CTX)/Creatinine calculated using ((Month 3 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 3

Percent Change From Baseline in Urine Type II C-Tx /Creatinine at Month 6

Percent change from baseline to Month 6 in urine Type II collagen C-Telopeptide (CTX)/Creatinine calculated using ((Month 6 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 6

Percent Change From Baseline in Urine Type II C-Tx /Creatinine at Month 12

Percent change from baseline to Month 12 in urine Type II collagen C-Telopeptide (CTX)/Creatinine calculated using ((Month 12 value - Baseline value) / Baseline value ) x 100.

Time frame: Baseline, Month 12

Number of Participants With Anti-Denosumab Binding Antibodies

Serum from participants was tested for antibodies to denosumab by immuoassay at months 1, 3, 6 and 12. The number of participants with anti-denosumab antibodies at any assessment is reported.

Time frame: Assessed at Baseline and at Months 1, 3, 6 and 12.

Number of Participants With Anti-Denosumab Binding Antibody and Neutralizing Antibody

Serum from participants testing positive for anti-denosumab binding antibodies was tested in a cell-based bioassay for neutralizing activity against denosumab.

Time frame: Baseline to Month 12

Change From Baseline in Albumin at Month 1

Laboratory Chemistry Albumin

Time frame: Baseline, month 1

Change From Baseline in Albumin at Month 3

Laboratory chemistry albumin

Time frame: Baseline, month 3

Change From Baseline in Albumin at Month 6

Laboratory chemistry albumin

Time frame: Baseline, month 6

Change From Baseline in Albumin at Month 12

Laboratory chemistry albumin

Time frame: Baseline, month 12

Change From Baseline in Alkaline Phosphatase at Month 1

Laboratory chemistry alkaline phoshatatse

Time frame: Baseline, month 1

Change From Baseline in Alkaline Phosphatase at Month 3

Laboratory chemisrty alkaline phosphatase

Time frame: baseline, month 3

Change From Baseline in Alkaline Phosphatase at Month 6

Laboratory chemistry alkaline phosphatase

Time frame: baseline, month 6

Change From Baseline in Alkaline Phosphatase at Month 12

Laboratory chemistry alkaline phosphatase

Time frame: baseine, month 12

Change From Baseline in Bicarbonate at Month 1

Laboratory chemistry bicarbonate

Time frame: baseline, month 1

Change From Baseline in Bicarbonate at Month 3

Laboratory chemistry bicarbonate

Time frame: baseline, month 3

Change From Baseline in Bicarbonate at Month 6

Laboratory chemistry bicarbonate

Time frame: Baseline, month 6

Change From Baseline in Bicarbonate at Month 12

Laboratory chemistry bicarbonate

Time frame: Baseline, Month 12

Change From Baseline in Total Bilirubin at Month 1

Laboratory chemistry total bilirubin

Time frame: baseline, month 1

Change From Baseline in Total Bilirubin at Month 3

Laboratory chemistry total bilirubin

Time frame: Baseline, month 3

Change From Baseline in Total Bilirubin at Month 6

Laboratory chemistry total bilirubin

Time frame: Baseline, month 6

Change From Baseline in Total Bilirubin at Month 12

Laboratory chemistry total bilirubin

Time frame: Baseline, month 12

Change From Baseline in Blood Urea Nitrogen at Month 1

Laboratory chemistry blood urea nitrogen

Time frame: Baseline, month 1

Change From Baseline in Blood Urea Nitrogen at Month 3

Laboratory chemistry blood urea nitrogen

Time frame: Baseline, month 3

Change From Baseline in Blood Urea Nitrogen at Month 6

Laboratory chemistry blood urea nitrogen

Time frame: Baseline, month 6

Change From Baseline in Blood Urea Nitrogen at Month 12

Laboratory chemistry blood urea nitrogen

Time frame: baseline, month 12

Change From Baseline in Calcium at Month 1

Laboratory chemistry calcium

Time frame: baseline. month 1

Change From Baseline in Calcium at Month 3

Laboratory chemistry calcium

Time frame: Baseline, month 3

Change From Baseline in Calcium at Month 6

Laboratory chemistry calcium

Time frame: baseline, month 6

Change From Baseline in Calcium at Month 12

Laboratory chemistry calcium

Time frame: Baseline, month 12

Change From Baseline in Calcium (Corrected) at Month 1

Laboratory chemistry albumin-adjusted calcium

Time frame: Baseline, month 1

Change From Baseline in Calcium (Corrected) at Month 3

Laboratory chemistry albumin-adjusted calcium

Time frame: baseline, month 3

Change From Baseline in Calcium (Corrected) at Month 6

Laboratory chemistry albumin-adjusted calcium

Time frame: Baseline, Month 6

Change From Baseline in Calcium (Corrected) at Month 12

Laboratory chemistry albumin-adjusted calcium

Time frame: Baselien, Month 12

Change From Baseline in Chloride at Month 1

Laboratory chemistry chloride

Time frame: baseline, month 1

Change From Baseline in Chloride at Month 3

Laboratory chemistry chloride

Time frame: Baseline, month 3

Change From Baseline in Chloride at Month 6

Laboratory chemistry chloride

Time frame: Baseline, month 6

Change From Baseline in Chloride at Month 12

Laboratory chemistry chloride

Time frame: Baseline, month 12

Change From Baseline in Creatinine at Month 1

Laboratory chemistry creatinine

Time frame: Baseline, month 1

Change From Baseline in Creatinine at Month 3

Laboratory chemistry creatinine

Time frame: Baseline, month 3

Change From Baseline in Creatinine at Month 6

Laboratory chemistry creatinine

Time frame: Baseline, month 6

Change From Baseline in Creatinine at Month 12

Laboratory chemistry creatinine

Time frame: Baseline, month 12

Change From Baseline in Gamma-Glutamyl Transferase at Month 1

Laboratory chemistry gamma-glutamyl transferase

Time frame: Baseline, month 1

Change From Baseline in Gamma-Glutamyl Transferase at Month 3

Laboratory chemistry gamma-glutamyl transferase

Time frame: Baseline, month 3

Change From Baseline in Gamma-Glutamyl Transferase at Month 6

Laboratory chemistry gamma-glutamyl transferase

Time frame: Baseline, month 6

Change From Baseline in Gamma-Glutamyl Transferase at Month 12

Laboratory chemistry gamma-glutamyl transferase

Time frame: Baseline, month 12

Change From Baseline in Glucose at Month 1

Laboratory chemistry glucose

Time frame: Baseline, month 1

Change From Baseline in Glucose at Month 3

Laboratory chemistry glucose

Time frame: Baseline, month 3

Change From Baseline in Glucose at Month 6

Laboratory chemistry glucose

Time frame: Baseline, month 6

Change From Baseline in Glucose at Month 12

Laboratory chemistry glucose

Time frame: baseline, month 12

Change From Baseline in Potassium at Month 1

Laboratory chemistry potassium

Time frame: Baseline, month 1

Change From Baseline in Potassium at Month 3

Laboratory chemistry potassium

Time frame: Baseline, month 3

Change From Baseline in Potassium at Month 6

Laboratory chemistry potassium

Time frame: Baseline, month 6

Change From Baseline in Potassium at Month 12

Laboratory chemistry potassium

Time frame: Baseline, month 12

Change From Baseline in Magnesium at Month 1

Laboratory chemistry magnesium

Time frame: Baseline, month 1

Change From Baseline in Magnesium at Month 3

Laboratory chemistry magnesium

Time frame: Baseline, month 3

Change From Baseline in Magnesium at Month 6

Laboratory chemistry magnesium

Time frame: Baseline, month 6

Change From Baseline in Magnesium at Month 12

Laboratory chemistry magnesium

Time frame: Baseline, month 12

Change From Baseline in Sodium at Month 1

Laboratory chemistry sodium

Time frame: Baseline, month 1

Change From Baseline in Sodium at Month 3

Time frame: Baseline, Month 3

Change From Baseline in Sodium at Month 6

Laboratory chemistry sodium

Time frame: Baseline, month 6

Change From Baseline in Sodium at Month 12

Laboratory chemistry sodium

Time frame: Baseline, month 12

Change From Baseline in Phosphorus at Month 1

Laboratory chemistry phosphorus

Time frame: Baseline, month 1

Change From Baseline in Phosphorus at Month 3

Laboratory chemistry phosphorus

Time frame: Baseline, month 3

Change From Baseline in Phosphorus at Month 6

Laboratory chemistry phosphorus

Time frame: Baseline, month 6

Change From Baseline in Phosphorus at Month 12

Time frame: Baseline, month 12

Change From Baseline in Total Protein at Month 1

Laboratory chemistry total protein

Time frame: Baseline, month 1

Change From Baseline in Total Protein at Month 3

Laboratory chemistry total protein

Time frame: Baseline, month 3

Change From Baseline in Total Protein at Month 6

Laboratory chemistry total protein

Time frame: Baseline, month 6

Change From Baseline in Total Protein at Month 12

Laboratory chemistry total protein

Time frame: Baseline, month 12

Change From Baseline in Aspartate Amino Transferase at Month 1

Laboratory chemistry aspartate amino transferase

Time frame: Baseline, month 1

Change From Baseline in Aspartate Amino Transferase at Month 3

Laboratory chemistry aspartate amino transferase

Time frame: Baseline, month 3

Change From Baseline in Aspartate Amino Transferase

Laboratory chemistry aspartate amino transferase

Time frame: Baseline, month 6

Change From Baseline in Aspartate Amino Transferase at Month 12

Laboratory chemistry aspartate amino transferase

Time frame: Baseline, month 12

Change From Baseline in Alanine Amino Transferase at Month 1

Laboratory chemistry alanine amino transferase

Time frame: Baseline, month 1

Change From Baseline in Alanine Amino Transferase at Month 3

Laboratory Chemistry alanine amino transferase

Time frame: Baseline, month 3

Change From Baseline in Alanine Amino Transferase at Month 6

Laboratory chemistry alanine amino transferase

Time frame: Baseline, month 6

Change From Baseline in Alanine Amino Transferase at Month 12

Laboratory chemistry alanine amino transferase

Time frame: Baseline, month 12

Change From Baseline in Basophils at Month 1

Laboratory hematology basophils

Time frame: baseline, month 1

Change From Baseline in Basophils at Month 3

Laboratory hematology basophils

Time frame: Baseline, month 3

Change From Baseline in Basophils at Month 6

Laboratory hematology basophils

Time frame: Baseline, month 6

Change From Baseline in Basophils at Month 12

Laboratory hematology basophils

Time frame: Baseline, month 12

Change From Baseline in Eosinophils at Month 1

Laboratory hematology eosinophils

Time frame: Baseline, month 1

Change From Baseline in Eosinophils at Month 3

Laboratory hematology eosinophils

Time frame: Baseline, month 3

Change From Baseline in Eosinophils at Month 6

Laboratory hematology eosinophils

Time frame: Baseline, month 6

Change From Baseline in Eosinophils at Month 12

Laboratory hematology eosinophils

Time frame: Baseline, month 12

Change From Baseline in Hematocrit at Month 1

Laboratory hematology hematocrit

Time frame: Baseline, month 1

Change From Baseline in Hematocrit at Month 3

Laboratory hematology hematocrit

Time frame: Baseline, month 3

Change From Baseline in Hematocrit at Month 6

Laboratory hematology hematocrit

Time frame: Baseline, month 6

Change From Baseline in Hematocrit at Month 12

Laboratory hematology hematocrit

Time frame: Baseline, month 12

Change From Baseline in Hemoglobin at Month 1

Laboratory hematology hemoglobin

Time frame: Baseline, month 1

Change From Baseline in Hemoglobin at Month 3

Laboratory hematology hemoglobin

Time frame: Baseline, month 3

Change From Baseline in Hemoglobin at Month 6

Laboratory hematology hemoglobin

Time frame: Baseline, month 6

Change From Baseline in Hemoglobin at Month 12

Laboratory hematology hemoglobin

Time frame: Baseline, month 12

Change From Baseline in Lymphocytes at Month 1

Laboratory hematology lymphocytes

Time frame: Baseline, month 1

Change From Baseline in Lymphocytes at Month 3

Laboratory hematology lymphocytes

Time frame: Baseline, month 3

Change From Baseline in Lymphocytes at Month 6

Laboratory hematology lymphocytes

Time frame: Baseline, month 6

Change From Baseline in Lymphocytes at Month 12

Laboratory hematology lymphocytes

Time frame: Baseline, month 12

Change From Baseline in Monocytes at Month 1

Laboratory hematology monocytes

Time frame: Baseline, month 1

Change From Baseline in Monocytes at Month 3

Laboratory hematology monocytes

Time frame: Baseline, month 3

Change From Baseline in Monocytes at Month 6

Laboratory hematology monocytes

Time frame: Baseline, month 6

Change From Baseline in Monocytes at Month 12

Laboratory hematology monocytes

Time frame: Baseline, month 12

Change From Baseline in Total Neutrophils at Month 1

Laboratory hematology total neutrophils

Time frame: Baseline, month 1

Change From Baseline in Total Neutrophils at Month 3

Laboratory hematology total neutrophils

Time frame: Baseline, month 3

Change From Baseline in Total Neutrophils at Month 6

Laboratory hematology total neutrophils

Time frame: Baseline, month 6

Change From Baseline in Total Neutrophils at Month 12

Laboratory hematology total neutrophils

Time frame: Baseline, month 12

Change From Baseline in Platelets at Month 1

Laboratory hematology platelets

Time frame: Baseline, month 1

Change From Baseline in Platelets at Month 3

Laboratory hematology platelets

Time frame: Baseline, month 3

Change From Baseline in Platelets at Month 6

Laboratory hematology platelets

Time frame: Baseline, month 6

Change From Baseline in Platelets at Month 12

Laboratory hematology platelets

Time frame: Baseline, month 12

Change From Baseline in Red Blood Cells at Month 1

Laboratory hematology red blood cells

Time frame: Baseline, month 1

Change From Baseline in Red Blood Cells at Month 3

Laboratory hematology red blood cells

Time frame: Baseline, month 3

Change From Baseline in Red Blood Cells at Month 6

Laboratory hematology red blood cells

Time frame: Baseline, month 6

Change From Baseline in Red Blood Cells at Month 12

Laboratory hematology red blood cells

Time frame: Baseline, month 12

Change From Baseline in White Blood Cells at Month 1

Laboratory hematology white blood cells

Time frame: Baseline, month 1

Change From Baseline in White Blood Cells at Month 3

Laboratpry hematology white blood cells

Time frame: Baseline, month 3

Change From Baseline in White Blood Cells at Month 6

Laboratory hematology white blood cells

Time frame: Baseline, month 6

Change From Baseline in White Blood Cells at Month 12

Laboratory hematology white blood cells

Time frame: Baseline, month 12

Number of Participants With Laboratory Common Terminology Criteria for Adverse Events (CTCAE) Grade Greater or Equal to 3

Participants with laboratory toxicity of grade 3 or 4, graded according to the Common Terminology Criteria for Adverse Events, version 3.0, on the following general guideline: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death related to AE.

Time frame: Month 1, month 3, month 6, month 12