Musculoskeletal Ultrasound Assessment of Therapeutic Response of Tofacitinib in Rheumatoid Arthritis Patients
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Sponsor: University of California, Los Angeles

 
 
 
 
Study Title 
 
Musculoskeletal Ultrasound Assessment of Therapeutic Response of Tofacitinib 
in Rheumatoid Arthritis Patients 
 
 
NCT 
02321930 
 
 
Date of Protocol 
 
Version 3 dated 11 May 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
 
 
 
 
 
 
 
 
 
 
 
Study Title 
 
Musculoskeletal Ultrasound Assessment of Therapeutic Response of 
Tofacitinib in Rheumatoid Arthritis Patients 
 
 
Pfizer Study Drug 
Tofacitinib (Xeljanz®) 
 
Support Provided By 
Pfizer 
 
Investigator 
Veena K. Ranganath MD, MS 
 
Sub-Investigator 
David Elashoff, PhD 
 
Study Type 
Open-label Pilot Study 
 
Grant Request 
We are requesting both funding and drug 
 
Research Setting 
Single Site at UCLA 
 
Country of Primary Site 
USA 
 
 
 
 
 
 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
Brief Study Synopsis:              
 
A. Utility of Musculoskeletal Ultrasonography in RA Therapeutic Response 
Advances in drug development of small molecules, biologic agents, and disease 
modifying anti-rheumatic drugs (DMARDs) have improved disease activity, quality of 
life, and imaging outcomes in rheumatoid arthritis (RA). Although radiographic 
assessments of joint space narrowing and erosions of the hands/feet are considered the 
gold standard imaging outcome measure, musculoskeletal ultrasound (MSUS) is quickly 
becoming a valuable imaging modality to diagnose rheumatic disorders and monitor 
therapeutic response. 
MSUS use by rheumatologists is rapidly growing in the USA [4]. Ultrasound 
offers, for both patient and clinician, a safe, sensitive, cost-effective, and convenient 
modality for detection of synovitis. Importantly, sonography can be utilized at point of 
care and does not require use of contrast to detect vascularity. A recent ACR 
whitepaper outlined the current status of the use of sonography in American 
Rheumatology practice.  This paper and others have summarized the validity of use of 
musculoskeletal ultrasound in RA clinical trials studying the response to therapeutic 
agents [5-7]. MSUS is more sensitive than x-ray in detecting erosions and it has the 
added advantage at inferring inflammation in synovial tissues by detecting blood flow in 
tissues without the use of contrast agents. We hypothesize that MSUS derived 
measurements of synovitis (power Doppler [PDUS] and grey scale synovial hypertrophy 
[GSUS]) will serve as an early imaging marker of rheumatoid arthritis (RA) clinical 
response to treatment with tofacitinib.  Studies have yet to examine the utility of 
performing US to determine early RA therapeutic response in tofacitinib, thus a unique 
opportunity for investigation. 
As stated earlier, radiographic assessments of joint space narrowing and 
erosions of the hands/feet (measures of damage) are considered the gold standard 
imaging outcome measurement, largely because these measures are validated to 
measure change in randomized controlled trials (RCTs), with change shown to be 
associated with function and disability. However, appropriate and judicious use of RA 
therapeutics has improved outcomes to the point that radiographic progression is halted 
in a majority of patients.  In order to show a difference in structural damage between 2 
active RA treatments arms with radiographs requires a large sample size, and more 
importantly, this lack of sensitivity doesn’t allow use of radiographs to facilitate treatment 
decisions. Additional consideration for treatment decisions is that clinical composite 
measures such as DAS28, CDAI, and RAPID3 may not adequately reflect the totality of 
intra-articular inflammation contributing to joint damage. Understandably, the use of 
musculoskeletal US in detecting synovial vascularity and hypertrophy is rapidly 
becoming a valuable imaging modality to sensitively assess therapeutic response in RA 
[8, 9]. 
Sonography may also be useful in assessing response, where suppression of 
PDUS signal after administration of biologic agents suggests response to therapy [11, 
14], and persistence of Doppler signal may predict the risk of progressive erosive 
disease.  It is this feature that we hypothesize will be useful in determining which 
patients may or may not respond to tofacitinib.  Kume et al demonstrated the rapid 
response to 8mg/kg (maximum dose 800mg) Tocilizumab in biological therapy naive RA 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
patients who were non responsive to low dose prednisone and methotrexate. The 
investigators were able to predict DAS28 response at 24 weeks based on Doppler 
activity at two weeks. Non responders did not show any change in Doppler activity at 
two weeks [15]. Similar findings have been reported by other investigators who treated 
patients with active RA with other biologic and DMARD agents, though not yet with 
tofacitinib [11-13]. 
 
B. Utility of Vectra DA in RA Therapeutic Response 
Regrettably, there is no single laboratory, clinical or imaging measure that accurately 
anticipates response to therapy for patients with RA. Instead, complex composite 
disease activity measures (Disease Activity Score [DAS28/ESR]), quality of life 
measures (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and x-ray 
progression of disease (Sharp Scores) are all used simultaneously as outcome 
measures in clinical trials. Understandably, there is a strong push to find appropriate 
and feasible biomarkers in patients with RA that can predict early response to therapy. 
Some biomarkers have been suggested for evaluating early therapeutic response, i.e. 
C-Reactive Protein (CRP); however, due to the poor specificity of the tests they have 
only been used in combination with other clinical and imaging measures. The ability to 
detect which RA patients will be responders would be a significant advance in the 
management of RA. 
 
The multi-biomarker disease activity (MBDA) blood test (VectraDA TM; 
Crescendo Bioscience, Inc., South San Francisco, CA) is currently commercially 
available to assess RA disease activity. Serum from peripheral blood is processed and 
assayed for 12 protein biomarkers (VCAM-1, EGF, VEGF-A, IL-6, TNF-RI, MMP-1/3, 
YKL-40, Leptin, Resistin, SAA, and CRP). An algorithm of these 12 markers is utilized 
to characterize RA disease activity on a scale of 1-100 (the higher the number 
represents more disease activity). Due to ease of performing and interpreting the test, 
many community rheumatologists utilize this test to evaluate disease activity in their RA 
patients. However, much more work is needed to fully validate the use of MBDA. Due to 
intriguing recent data, the MBDA is gaining more notice by academicians that this 
biomarker may aid in therapeutic management of the RA patient. Based on several 
studies, correlation between DAS28, SDAI, and CDAI with the MBDA is moderate to 
good ranging from 0.5-0.84. Curtis et al in 2012 published findings that the MBDA 
correlated well with seropositive and seronegative RA patients. In addition, changes in 
MBDA scores at 6-12 weeks were significantly associated with ACR50 response rates 
and change in DAS28-CRP. MBDA was also assessed in a subcohort of the CAMERA 
study at baseline and 6 mos. In a multivariate analysis, a modified MBDA score (without 
CRP) was an independent predictor of disease activity, while CRP was not. Lastly, in a 
study published by van der Helm-van Mil et al., MBDA cut off of <25 was associated 
with limited radiographic progression over 12 months in the Leiden Early Arthritis 
Cohort. Patients who were in DAS28-CRP remission but had >25 MBDA scores were at 
an elevated risk for continued radiographic progression.  
 
C. Proposal: Utilization of Both MSUS and MBDA to Evaluate Response to Therapy 
with Tofacitinib 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
Thus, we propose to use musculoskeletal ultrasound and Vectra DA to examine initial 
response to tofacitinib to determine whether the early effect on synovitis (2 weeks 
and/or 1month) is predictive of the likelihood of achieving a response in patients at 3 
months, and whether this effect then correlates with timing and magnitude of response. 
To this end, we propose an open-label tofacitinib clinical study of 25 RA patients to 
evaluate the potential usefulness of US as an early indicator in measuring response. 
This proposal seeks to provide a better understanding of two general concepts: 
1) Early assessment of MSUS therapeutic response in patients starting tofacitinib, and 
2) Early evaluation of Vectra DA in determining clinical response with tofacitinib. 
 
Brief Study Rationale/Objectives: 
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. 
Table 1 
JOINT 
VIEW 
Power 
Doppler 
Synovitis 
B-mode 
Synovial 
Hypertrophy 
Wrists Bilateral 
(Position: 0 Deg) 
Dorsal Longitudinal/Short 
Midline 
(Radio carpal, intercarpal) 
X 
X 
MCPs (1-5) 
(Position: 0 Deg) 
Dorsal Long and Short 
X 
X 
Volar Longitudinal 
X 
X 
PIPs (2-5) and IP 
Dorsal/Volar Longitudinal 
X 
X 
MTPs (2-5) 
Dorsal Longitudinal 
X 
X 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
Knees Bilateral 
Medial Parapatellar Axial 
Oblique 
X 
X 
Lateral Parapatellar Axial 
Oblique 
X 
X 
 
 
Primary Aims: 
AIM 1: To determine whether MSUS inflammatory scores (PDUS and GSUS) or MBDA 
improve in response to treatment with tofacitinib over 3 months. 
 
AIM 2: To assess the association between the change in ultrasound measures/MBDA 
and change in DAS28-ESR and/or CDAI. 
 
Exploratory Aims: 
AIM 3: To evaluate if early changes in MSUS or MBDA can predict response at 3 
months with tofacitinib. 
 
AIM 4: To assess the correlation between MSUS scores and MBDA at baseline and 2 
weeks. 
 
Primary Endpoints 
3 month change in MSUS power Doppler 
3 month change in MBDA 
3 month change in DAS28/ESR 
3 month change in CDAI  
 
MSUS Outcome measures: Total power Doppler synovitis score of 34 joints (range 0-
102), Total B-mode synovial hypertrophy score of 34 joints (range 0-102), Composite of 
power Doppler + synovial hypertrophy of 34 joints (range 0-204) 
Statistical Methods 
Sample size is for the primary endpoint of change in PDUS scores from baseline to 
month 3.  
We based our sample sizes on the ultrasound and disease activity data collected from 
another IIR (unpublished). Mean PDUS scores changed from 7.3 to 3.9 after 3 months 
of treatment with a standard deviation of the changes of 3.3. Assuming this same effect 
size and with 25 total patients we estimate 99% power to detect differences in PDUS 
from baseline to month 3 assuming a two-sided paired t-test with 0.05 level of 
significance. If 25% attenuation in effect size is observed, our sample of 25 will have 
95% power to detect differences in PDUS from baseline to month 3 assuming a two-
sided paired t-test with 0.05 level of significance. 
A Pearson correlation coefficient of 0.51 was observed between PDUS and 
DAS28/ESR at baseline in the other IIR cohort. Based on this correlation coefficient, we 
estimate that we will have 77% power to detect correlation between DAS28/ESR and 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
PDUS with a sample size of 25, assuming a two-sided Pearson correlation with 0.05 
level of significance. 
 
Aim 1. We will use Wilcoxon signed rank tests to compare MSUS and MBDA scores 
between baseline and the 3 month time points.  
Aim 2. We will use linear regression to model the outcomes of change (baseline  -  3 
months) in disease activity measures (DAS-28 and CDAI). The independent variables to 
be considered in these models will be change in MSUS/MBDA (baseline  -  3 months) 
scores. Mixed effects models will also be used to assess the longitudinal association 
between disease activity and MSUS/MBDA scores. 
Aim 3. We will use linear regression to model the outcomes of change (baseline  -  3 
months) in disease activity measures (DAS-28 and CDAI). The independent variables to 
be considered in these models will be change in MSUS/MBDA (baseline  -  2 week) 
scores. For each of the outcomes we will use forward stepwise model selection to 
identify the best combination of MSUS/MBDA measures to predict response. We will 
assess the predictive ability of the marker by computing the model R-squared and the 
estimated prediction accuracy (median absolute residuals).  
Aim 4. We will use Spearman correlation coefficients to evaluate the correlation 
between baseline, 2-week, and baseline-2 week MSUS scores versus MBDA. 
 
Inclusion/Exclusion Criteria 
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 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. If not on DMARD, the patient can opt 
for monotherapy with tofacitinib or combination therapy. 
5) Power Doppler score of >=10 (out of 34 joints assessed) 
6) Female subjects of childbearing potential must test negative for pregnancy 
7) Male and female subjects of childbearing potential and at risk for pregnancy must 
agree to use contraception throughout the study. 
8) Negative QuantiFERON Gold test performed at screening 
a. This is required unless the subject has been adequately treated for active 
or latent tuberculosis or a negative QuantiFERON Gold was previously 
performed and documented within the 3 months prior to screening. 
b. A negative tuberculin skin test (TST) <5 mm induration can be substituted 
for the QuantiFERON Gold 
 
Exclusion Criteria: 
1) 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.) 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
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: 
a. Evidence of hematopoietic disorder or hemoglobin <9 g/dL 
b. Absolute lymphocyte count <0.75 x 109/L (<750/mm3) 
c. Absolute neutrophil count <1.2 x 109/L (<1200/mm3) 
d. Platelet count <100 x 109/L (<100,000/mm3) 
e. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) 
>1.5 times the upper limit of normal (x ULN) 
f. 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) 
Table 2 
Procedure 
Pre-
Treatment 
Screening 
Visit 1 
During 
Treatm
ent 
Visit 2 
Baselin
e Visit 
During 
Treatment 
Visit 3 
2 Week 
Visit 
During 
Treatment 
Visit 4 
6 Week 
Visit 
During 
Treatment 
Visit 5 
12 Week 
Visit 
Safety 
Follow-
up   
Visit Time Window 
 
 
+/- 2 
weeks 
+/-2 weeks 
+/- 2 weeks 
 
Eligibility 
Assessments 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
Chest X-ray (if not 
done within 3 mos) 
X 
 
 
 
 
 
QuantiFERON(if not 
done within 3 mos) a 
X 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
Targeted Physical 
Examination 
 
X 
X 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
Procedure 
Pre-
Treatment 
Screening 
Visit 1 
During 
Treatm
ent 
Visit 2 
Baselin
e Visit 
During 
Treatment 
Visit 3 
2 Week 
Visit 
During 
Treatment 
Visit 4 
6 Week 
Visit 
During 
Treatment 
Visit 5 
12 Week 
Visit 
Safety 
Follow-
up   
Concomitant 
Medication 
X 
X 
X 
X 
X 
 
Assessment of Signs 
and Symptoms 
 
X 
X 
 
X 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 
CBC and Chem Panel 
Tests3 
X 
X 
X 
(X) 
X 
 
Lipid Panel 
 
X 
 
 
X 
 
Cocci IgG, IgM EIA 
X 
 
 
 
 
 
HIV, Hepatitis B and 
C Serologies (if not 
done within 3 mos) 
X 
 
 
 
 
 
Rheumatoid Factor 
and CCP 
X 
 
 
 
 
 
hsCRP 
X 
X 
X 
 
X 
 
ESR 
X 
X 
X 
 
X 
 
Urine Pregnancy Test 
X 
X 
X 
 
X 
 
Vectra DA 
 
X 
X 
 
X 
 
Biomarkers 
  
Efficacy 
Assessments 
X 
X 
X 
 
X 
 
Joint Assessment 
X 
X 
X 
 
X 
 
MD Global 
X 
X 
X 
 
X 
 
Patient Global 
X 
X 
X 
 
X 
 
CDAI 
X 
X 
X 
 
X 
 
DAS28/ESR 
X 
X 
X 
 
X 
 
HAQ-DI and other 
questionnaires 
X 
X 
X 
 
X 
 
Ultrasound 34 joint 
Acquisition 
X 
X 
X 
 
X 
 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
Procedure 
Pre-
Treatment 
Screening 
Visit 1 
During 
Treatm
ent 
Visit 2 
Baselin
e Visit 
During 
Treatment 
Visit 3 
2 Week 
Visit 
During 
Treatment 
Visit 4 
6 Week 
Visit 
During 
Treatment 
Visit 5 
12 Week 
Visit 
Safety 
Follow-
up   
Ultrasound 34 joint 
Scoring 
X 
X 
X 
 
X 
 
 
a.  If QuantiFeron test cannot be performed, TB skin test can be done instead. 
 
1. If a chest X-ray or CT scan of chest was done within the past 3 months, there is 
no need to repeat. 
2. CBC and Chem panel laboratory tests do not have to be done if they were done 
within the past 4 weeks. 
3. Hepatitis B and C serologies do not have to be done if they were done within the 
past 3 months. 
4. Rheumatoid Factor and CCP test do not have to be done at screening if they 
were done previously. 
5. CBC and Chem panel at the 6-week visit may be done per PI discretion.  
 
** Study procedures may be repeated per PI discretion.  
 
Target Enrollment 
We plan to enroll 25 patients 
 
Treatment Plan or Dosing Regimen 
Open label tofacitinib 5mg po bid 
 
Study Duration 
3 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Tofacitinib Ultrasound Study 
 
 
 
 Version 3, DATE May 11, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix: Prohibited Concomitant Medications 
  
Prohibited drugs, including investigational compounds, require 
discontinuation for at least 7 days or 5 half-lives (whichever is longer) prior 
the baseline visit. Only systemically administered drugs listed below are 
prohibited; topical, ophthalmic, or intravaginal administration is allowed. 
 
Prohibited Concomitant Medications 
Potent CYP3A/CYP2C19 Inhibitors  Moderate or Potent CYP3A 
Inducers  
Protease inhibitors:  
Protease inhibitors:  
indinavir (Crixivan)  
efavirenz (Sustiva)*  
nelfinavir (Viracept)  
nevirapine (Viramune)*  
ritonavir (Kaletra, Norvir)  
Anticonvulsants:  
Saquinavir (Invirase)  
barbiturates*  
Macrolide antibiotics:  
phenobarbital*  
clarithromycin (Biaxin, Prevpac)  
phenytoin (Dilantin, Phenytek)  
telithromycin (Ketek)  
carbamazepine (Carbatrol, 
Tegretol)*  
Other antibiotics:  
Antibiotics:  
chloramphenicol  
rifampicin/rifampin (Rifadin, 
Rifamate)  
Antifungals:  
rifabutin (Mycobutin)*  
fluconazole (Diflucan)  
voriconazole (Vfend)  
rifapentene (Priftin)*  
ketoconazole (Nizoral)  
Antidepressants:  
itraconazole (Sporanox)  
St. John's Wort*  
Antidepressants:  
Other compounds:  
fluvoxamine (Luvox)  
modafinil (Provigil)  
nefazodone (Serzone)  
troglitazone (Rezulin)