Musculoskeletal Ultrasound Assessment of Therapeutic Response of Tofacitinib in Rheumatoid Arthritis Patients

Phase 4

Completed

• Conditions: Rheumatoid Arthritis
• Interventions: Drug: tofacitinib 5mg po bid

• Registration Number: NCT02321930
• Lead Sponsor: University of California, Los Angeles

Brief Summary

This proposal will evaluate if musculoskeletal ultrasound (MSUS) measures or multi-biomarker disease activity (MBDA) improve in patients treated with tofacitinib over 3 months, and whether early MSUS measures/MBDA can predict response to therapy.

Detailed Description

This is a pilot open-label trial of 25 RA patients treated with tofacitinib over 3 months. The patients meeting inclusion criteria will be started on tofacitinib 5mg po bid. Patients will be recruited from the UCLA Rheumatology Clinics. Inclusion criteria will include the following: meeting ACR 1987 RA criteria, DAS28≥3.2, age≥18, and PDUS\>10 (see below for more details). Patients who are deemed unsafe to enroll will be excluded. Ultrasound measures (PDUS/GSUS) and MBDA scores will be obtained at screen, baseline, 2 weeks, and 3 months. In addition, we will also obtain HAQ-DI, CDAI, and DAS28 at the same time points. In addition, we will have a 6 week visit for capturing adverse events, concomitant drugs, drug dispensation, and evaluation of adherence. Currently, there are several US measures to evaluate therapeutic response in RA patients that have been used in the literature. Some US studies evaluate all joints involved in RA, which is time consuming. At present, there is no consensus as to the ideal ultrasound scoring system. However, we will utilize a 34-joint US scoring system to evaluate response to therapy in this proposal (see Table 1). Our research team has expertise in MSUS (given several workshops/lectures nationally) and we have proficiency in designing/conducting MSUS clinical trials. We currently have 4 ultrasonography-rheumatologists at UCLA who are ACR certified in MSUS.

Study Timeline

• Study First Submitted: 2014-09-23
• Study First Submitted QC: 2014-12-16
• Study First Posted: 2014-12-22
• Study Start: 2016-02-16
• Primary Completion: 2017-09-29
• Study Completion: 2017-09-29
• Results First Submitted: 2019-01-18
• Status Verified: 2019-02
• Results First Submitted QC: 2019-02-27
• Last Update Submitted: 2019-02-27
• Results First Posted: 2019-03-19
• Last Update Posted: 2019-03-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 37

Inclusion Criteria

1. Patient must meet 1987 ACR criteria
2. Age > 18 years of age
3. Baseline DAS28/ESR>=3.2
4. Stable concomitant DMARDs
5. Stable prednisone <10mg or equivalent
6. Power Doppler score of >=10
7. Female subjects of childbearing potential must test negative for pregnancy
8. Male and female subjects of childbearing potential must agree to use contraception throughout the study
9. Negative QuantiFERON Gold test at screening

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Exclusion Criteria

1. No active TB

2. Prednisone >10 mg

3. Pregnancy or breast feeding

4. Prior treatment with tofacitinib

5. Concomitant biologic therapy (TNF inhibitors, IL-6 inhibitors, etc.)

6. Active infection with HIV, hepatitis B or C, or herpes zoster

7. Subjects with any uncontrolled clinically significant laboratory abnormality or any of the following laboratory abnormalities:

   1. Evidence of hematopoietic disorder or hemoglobin <9 g/dL
   2. Absolute lymphocyte count <0.75 x 109/L (<750/mm3)
   3. Absolute neutrophil count <1.2 x 109/L (<1200/mm3)
   4. Platelet count <100 x 109/L (<100,000/mm3)
   5. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >1.5 times the upper limit of normal (x ULN)
   6. Estimated GFR <40 ml/min

8. Subjects who have received live or live attenuated vaccines within 6 weeks prior to the first dose of study drug (or the zoster vaccine)

9. Subjects who require concomitant treatment with medications that are potent inhibitors of cytochrome P450 3A4 (CYP3A4), both moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19, and potent CYP inducers (See Appendix)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
tofacitinib 5mg po bid	tofacitinib 5mg po bid	Open label with tofacitinib 5mg po bid

Primary Outcome Measures

Name	Time	Method
PDUS	Baseline, Week 2, Month 3	30 joints will be evaluated using a 0 to 3 point scale for each joint and the sum of these represents PDUS. The Power Doppler Synovitis Score (PDUS) ranges from 0 to 90. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. A higher value of the total score for PDUS represents more severe disease level.
CDAI	Baseline, Week 2, Month 3	CDAI was derived as the sum of the following: tender joint count (TJC), swollen joint count (SJC), participant global assessment (PGA) of disease activity, and physician assessment of disease activity. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 millimeters (mm) and rounded to the nearest centimeter (cm) on a visual analog scale (VAS), where higher scores indicate greater perceived disease activity. The total CDAI score range was 0-76, where higher scores indicate increased disease activity.
GSUS	Baseline, Week 2, Month 3	30 joints will be evaluated using a 0 to 3 point scale for each joint and the sum of these represents GSUS. The grey scale synovial hypertrophy score (GSUS) ranges from 0 to 90. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. A higher value of the total score for GSUS represents more severe disease level.
DAS28/ESR	Baseline, Week 2, Month 3	TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. Patient Global Assessment of disease activity was scored 0-100 millimeters (mm) and rounded to the nearest centimeter (cm) on a visual analog scale (VAS), where higher scores indicate greater perceived disease activity. ESR lab value were included in the total calculation. The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation.The scale ranges from 0 to 9.4, where higher values represent a higher disease activity.The complete formula to calculate DAS28/ESR is 0.56\*sqrt(TJC) + (0.28\*sqrt(SJC)) + (0.7\*ln(ESR)) + (0.014\*Patient Global\*10).

Secondary Outcome Measures

Name	Time	Method
MBDA	Baseline, Week 2, Month 3	The multi-biomarker disease activity (MBDA) blood test assesses RA disease activity. An algorithm of 12 markers is used to characterize RA disease activity on a scale of 1-100, where a score of 100 represents the highest level of disease activity present.

Trial Locations

Locations (1)

UCLA David Geffen School of Medicine, Division of Rheumatology; 🇺🇸 Los Angeles, California, United States