Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis
Brief summary
The purpose of this research study is to determine if a change in inflammation or baseline inflammation seen on the ultrasound is a good indicator of how rheumatoid arthritis patients respond to TCZ 4mg/kg and whether early prediction of dose escalation is possible by utilizing ultrasound inflammatory measures.
Detailed description
This is a 24-week, double blind open label clinical trial study to evaluate 57 active Rheumatoid Arthritis (RA) patients who have moderate to severe disease activity with total Power Doppler Ultrasound (PDUS) \>10 of 34 joints evaluated by Ultrasound (US) (at screening to enter into the study). All patients will begin treatment with tocilizumab at a dose of 4mg/kg. Two study sites will recruit patients (UCLA and UF) using the same protocol, after standardizing US acquisition methods, as well as scoring. US synovitis scores will be acquired at screening, baseline, and pre-infusion at 4, 12, 16, and 24 weeks, to be able to determine whether change in pre-infusion synovitis score at 4 weeks can be used to predict change in disease activity at 12 weeks. This will provide evidence to whether such reading is useful in predicting which patients may require escalation of dose from 4 to 8 mg/kg. At 12 weeks, patients not meeting low disease activity within the 4mg/kg (disease activity score DAS28/ Erythrocyte Sedimentation Rate (ESR)-4item\<3.2) will increase the tocilizumab dose to 8mg/kg (maximum dose 800mg) in a blinded manner to enable evaluation of these US-focused objectives in the context of the current FDA-approved label. The ultrasound scorer will not know information about patient's disease activity (Tender Joint Count (TJC), Swollen Joint Count (SJC), labs etc) or if there was dose escalation at 12 weeks. The clinical assessor of disease activity will be blinded to the ultrasound scores. Additionally, the patient will also be blinded to dose escalation. If patients in the 4mg/kg arm achieve DAS28\<3.2 at 12 weeks, patients will continue with their current dose for the duration of the study. Please see the below Table for details on the blinding plan.
Interventions
DRUGTocilizumab
All subjects will start at 4mg/kg. After 3 months, if DAS28 \> 3.2, dosage will be escalated to 8 mg/kg.
Sponsors
Genentech, Inc.
University of California, Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must have rheumatoid arthritis. Patients will be included in the trial based on the following criteria: 1. Patient must meet 1987 American College of Rheumatology (ACR) criteria, 2. Age \> 18 years of age, 3. Baseline DAS28/ESR\>4.4, 4. Stable concomitant DMARDs for more than 1 month (methotrexate, leflunomide, plaquenil, sulfasalazine, or no DMARDs). However, if the patient is not on DMARD, history of DMARD use required. 1. If not on DMARD (and the patient satisfies the above statement), the patient can opt for monotherapy with tocilizumab or combination therapy OR 2. If on biologic monotherapy, can opt for monotherapy with tocilizumab or DMARD combination therapy (ie. patients cannot be on biologic with TCZ) 6\) Power Doppler score of \>10 at screening. General Medical Concerns: * Normal organ function, except if abnormal due to the disease under investigation * Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment. * Subject has provided written informed consent.
Exclusion criteria
A patient will be excluded if the answer to any of the following statements is yes. General: 1. Major surgery (including joint surgery) within 8 weeks prior to baseline or planned major surgery within 6 months after baseline. Excluded Previous or Concomitant Therapy: 2. Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of baseline. 3. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3. 4. Previous treatment with anti-CD19 and anti-CD20 within 6 months of start of the study. 5. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline. 6. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline. 7. Previous treatment with TCZ. 8. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation. 9. Use of prednisone \> 10mg at baseline. Exclusions for General Safety: 10. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies. 11. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease.) 12. Current liver disease as determined by principal investigator unless related to primary disease under investigation 13. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds). 14. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of baseline or oral antibiotics within 2 weeks prior to baseline. 15. Active Tuberculosis (TB) requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for tuberculosis with no recurrence in 3 years are permitted. 16. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation. 17. Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 5 years. 18. Pregnant women or nursing (breast feeding) mothers. 19. Patients with reproductive potential not willing to use an effective method of contraception. 20. History of alcohol, drug or chemical abuse within 1 year prior to screening. 21. Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation. 22. Patients with lack of peripheral venous access. 23. Body weight of \> 150 kg. Laboratory
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102) | Baseline, 3 Month | 34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Power Doppler scores. This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline to Month 3 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints | Baseline, 3 Month | 34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Synovial Hypertrophy Scores. This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level. |
| Baseline to Month 6 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints | Baseline, 6 Month | 34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Synovial Hypertrophy Scores. This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level. |
| Baseline to Month 3 Change in DAS28/ESR | Baseline, 3 month | 28 joints will be evaluated for Tender Joint Count (TJC) and Swollen Joint Count (SJC) as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 3 Month Disease Activity Score (DAS) scores. The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease. |
| Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102) | Baseline, 6 Month | 34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Power Doppler scores. This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level. |
| Baseline to Month 3 Change in CDAI | Baseline, 3 month | 28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 3 Month CDAI scores. The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity. |
| Baseline to Month 6 Change in CDAI | Baseline, 6 Month | 28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 6 Month CDAI scores. The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity. |
| Baseline to Month 6 Change in DAS28/ESR | Baseline, 6 Month | 28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 6 Month DAS scores. The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited through printed and internet advertisements, direct recruitment of study participants, referrals, review of medical records to identify potential participants, and through IRB approved screening protocol and IRB approved study. Patients were recruited starting on 9/24/14. The recruitment continued through November of 2016.
Pre-assignment details
16 did not pass inclusion criteria, these patients were not able to be assigned to a study arm: 8 had PDUS\<10 4 lab values outside limits 1. pregnant 2. changed their mind 1 was taking prednisone. Also: 4 other patients were assigned to the study arm but were deleted from the study due to the considerations mentioned in the protocol
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab All subjects will receive tocilizumab.
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 \> 3.2, dosage will be escalated to 8 mg/kg. | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Moved out of state | 1 |
| Overall Study | Patient concerned about mental health | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Tocilizumab |
|---|---|
| Age, Continuous | 51.87 years STANDARD_DEVIATION 15.16 |
| Clinical Disease Activity Index (CDAI) | 39.04 units on a scale STANDARD_DEVIATION 11.9 |
| Disease Activity Score All Joints (DAS28)/ Erythrocyte Sedimentation Rate (ESR) | 6.30 units on a scale STANDARD_DEVIATION 1.03 |
| Disease duration | 9.94 years STANDARD_DEVIATION 7.5 |
| Health Assessment Questionnaire- Disability Index (HAQ-DI) | 1.47 units on a scale STANDARD_DEVIATION 0.6 |
| Max Joint Grey-Scale Ultrasound (GSUS) | 43.61 units on a scale STANDARD_DEVIATION 14.68 |
| Max Joint Power Doppler Ultrasound (PDUS) | 29.59 units on a scale STANDARD_DEVIATION 16.06 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 34 Participants |
| Region of Enrollment United States | 54 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 54 |
| other Total, other adverse events | 51 / 54 |
| serious Total, serious adverse events | 1 / 54 |
Outcome results
Primary
Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)
34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Power Doppler scores. This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.
Time frame: Baseline, 3 Month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102) | 6.84 units on a scale | Standard Deviation 13.09 |
Secondary
Baseline to Month 3 Change in CDAI
28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 3 Month CDAI scores. The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.
Time frame: Baseline, 3 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 3 Change in CDAI | 9.64 units on a scale | Standard Deviation 10.72 |
Secondary
Baseline to Month 3 Change in DAS28/ESR
28 joints will be evaluated for Tender Joint Count (TJC) and Swollen Joint Count (SJC) as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 3 Month Disease Activity Score (DAS) scores. The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.
Time frame: Baseline, 3 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 3 Change in DAS28/ESR | 1.20 units on a scale | Standard Deviation 1.08 |
Secondary
Baseline to Month 3 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints
34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Synovial Hypertrophy Scores. This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.
Time frame: Baseline, 3 Month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 3 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints | 5.26 units on a scale | Standard Deviation 12.55 |
Secondary
Baseline to Month 6 Change in CDAI
28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 6 Month CDAI scores. The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.
Time frame: Baseline, 6 Month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 6 Change in CDAI | 16.70 units on a scale | Standard Deviation 12.27 |
Secondary
Baseline to Month 6 Change in DAS28/ESR
28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 6 Month DAS scores. The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.
Time frame: Baseline, 6 Month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 6 Change in DAS28/ESR | 2.32 units on a scale | Standard Deviation 1.22 |
Secondary
Baseline to Month 6 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints
34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Synovial Hypertrophy Scores. This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.
Time frame: Baseline, 6 Month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 6 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints | 11.00 units on a scale | Standard Deviation 15.32 |
Secondary
Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)
34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Power Doppler scores. This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.
Time frame: Baseline, 6 Month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mean Change of Total Power Doppler Synovitis Score 3 Month | Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102) | 13.16 units on a scale | Standard Deviation 15.68 |