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Musculoskeletal Ultrasound in Predicting Early Dose Titration With Tocilizumab (RASTS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01717859
Recruitment Status : Completed
First Posted : October 31, 2012
Results First Posted : November 29, 2018
Last Update Posted : May 15, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Dr. Veena Ranganath, University of California, Los Angeles

Tracking Information
First Submitted Date  ICMJE October 19, 2012
First Posted Date  ICMJE October 31, 2012
Results First Submitted Date  ICMJE July 9, 2018
Results First Posted Date  ICMJE November 29, 2018
Last Update Posted Date May 15, 2019
Study Start Date  ICMJE September 2014
Actual Primary Completion Date April 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 26, 2012)
Change in total power Doppler synovitis score of 28 joints (range 0-42) [ Time Frame: Baseline, 1 Month ]
28 joints will be evaluated.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
  • Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102) [ Time Frame: 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 Total B-mode Synovial Hypertrophy Score of 34 Joints [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 DAS28/ESR [ Time Frame: 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.
  • Baseline to Month 3 Change in CDAI [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 26, 2012)
  • Change in total B-mode synovial hypertrophy score of 28 joints (range 0-42) [ Time Frame: Baseline, 1 Month ]
    28 joints will be evaluated.
  • Change in composite of power Doppler + synovial hypertrophy of 28 joints (range 0-84) [ Time Frame: Baseline, 1 Month ]
    28 joints will be evaluated.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Musculoskeletal Ultrasound in Predicting Early Dose Titration With Tocilizumab
Official Title  ICMJE Musculoskeletal Ultrasound in Predicting Early Dose Titration With Tocilizumab
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE Drug: Tocilizumab
All subjects will start at 4mg/kg. After 3 months, if DAS28 > 3.2, dosage will be escalated to 8 mg/kg.
Other Name: Actemra
Study Arms  ICMJE Tocilizumab
All subjects will receive tocilizumab.
Intervention: Drug: Tocilizumab
Publications * Choate EA, Kaeley GS, Brook J, Altman RD, FitzGerald JD, Floegel-Shetty AR, Elashoff DA, Ranganath VK. Ultrasound detects synovitis in replaced and other surgically operated joints in rheumatoid arthritis patients. BMC Rheumatol. 2020 Feb 3;4:8. doi: 10.1186/s41927-019-0107-2. eCollection 2020.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 30, 2018)
74
Original Estimated Enrollment  ICMJE
 (submitted: October 26, 2012)
51
Actual Study Completion Date  ICMJE April 2017
Actual Primary Completion Date April 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 Exclusion criteria (at screening):

  24. Serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 mg/dL (168 µmol/L) in male patients. Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30.
  25. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN)
  26. Total Bilirubin > ULN
  27. Platelet count < 100 x 109/L (100,000/mm3)
  28. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
  29. White Blood Cells < 3.0 x 109/L (3000/mm3)
  30. Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3)
  31. Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)
  32. Positive Hepatitis BsAg, or Hepatitis C antibody
  33. HIV positive
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01717859
Other Study ID Numbers  ICMJE ML28542
ML28542 ( Other Identifier: Genentech Inc. )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dr. Veena Ranganath, University of California, Los Angeles
Study Sponsor  ICMJE University of California, Los Angeles
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Principal Investigator: Veena Ranganath, MD, MS UCLA David Geffen School of Medicine, Division of Rheumatology
PRS Account University of California, Los Angeles
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP