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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02321930

Enrollment

Registered

2014-12-22

Start date

2016-02-16

Completion date

2017-09-29

Last updated

2019-03-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rheumatoid Arthritis

Keywords

Rheumatoid Arthritis, Musculoskeletal Ultrasound, Tofacitinib, biomarker

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.

Interventions

DRUGtofacitinib 5mg po bid

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

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)

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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

Measure	Time frame	Description
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.

Countries

United States

Participant flow

Recruitment details

Patients will be recruited from the UCLA Rheumatology Clinics. The patients meeting inclusion criteria were started on tofacitinib 5mg po bid. Patients were recruited starting on 2/16/2016. The recruitment continued through 5/17/2017.

Pre-assignment details

12 did not pass inclusion criteria, these patients were not able to be assigned to a study arm

Participants by arm

Arm	Count
Tofacitinib 5mg po Bid All subjects will receive tofacitinib. Tofacitinib: Subjects will receive tofacitinib 5mg po bid	25
Total	25

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Lost to Follow-up	1

Baseline characteristics

Characteristic	Tofacitinib 5mg po Bid
Age, Continuous	52 years STANDARD_DEVIATION 9.93
BMI	31.02 Kg/m^2 STANDARD_DEVIATION 10.76
Disease duration	10.36 years STANDARD_DEVIATION 9.73
Health Assessment Questionnaire- Disability Index (HAQ-DI)	1.37 units on a scale STANDARD_DEVIATION 0.7
Race/Ethnicity, Customized Asian	4 Participants
Race/Ethnicity, Customized Black	4 Participants
Race/Ethnicity, Customized Caucasian	10 Participants
Race/Ethnicity, Customized Hispanic	5 Participants
Race/Ethnicity, Customized Other	2 Participants
Region of Enrollment United States	25 participants
Seropositive	22 Participants
Sex: Female, Male Female	22 Participants
Sex: Female, Male Male	3 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 25
other Total, other adverse events	24 / 25
serious Total, serious adverse events	1 / 25

Outcome results

Primary

CDAI

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.

Time frame: Baseline, Week 2, Month 3

Arm	Measure	Group	Value (MEAN)	Dispersion
Tofacitinib 5mg po Bid	CDAI	Baseline	39.88 units on a scale	Standard Deviation 13.21
Tofacitinib 5mg po Bid	CDAI	Week 2	28.60 units on a scale	Standard Deviation 13.23
Tofacitinib 5mg po Bid	CDAI	Week 12	21.63 units on a scale	Standard Deviation 13.02