Mesenchymal Stem Cells in Early Rheumatoid Arthritis

This is a prospective, multicenter (with two performance sites under the auspices of Case
Western Reserve University Clinical and Translational Science Award (CWRU CTSA) at University
Hospitals and at MetroHealth Medical Center), double-blind, placebo-controlled,
interventional study to evaluate the safety and efficacy of allogeneic mesenchymal stem cells
(MSCs) infusion in 20 new onset Rheumatoid Arthritis (RA) patients with moderate to high
disease activity despite adequate doses of methotrexate (MTX) for 12 weeks (at least 10 weeks
of which has been at a dose of >/=15 mg per week). The study is a single dose, phase I
clinical trial, and this is the first time that this product will be infused in RA patients.
After a screening period, the baseline visit will be conducted. Patients will halt their
concomitant MTX 3 days prior to the MSC infusion and may resume their methotrexate at Day 7
following MSC infusion based on their disease activity score. This is a dose escalation study
of a total of 20 patients with three groups of five patients each and five placebo patients.
Patients will be randomized to receive MSC or placebo infusion using a computer-generated
randomization scheme that takes into account that there are two sites. The first cohort will
consist of a total of six patients. Of these six patients, five patients each will receive a
single infusion of 2 million/kg MSCs and one patient will receive placebo infusion. The
second cohort will include a total of seven patients, of these seven patients; five patients
will receive 4 million/kg MSCs and two patients who will receive placebo infusion. The final
cohort consists of a total of seven patients. Of these seven patients, five patients will
receive 6 million/kg allogeneic MSCs and two patients will receive placebo infusion. Infusion
will occur on Day 0. Post-infusion study visits will occur on Days 1 (Visit 3), 7 (Visit 4),
14 (Visit 5), 28 (Visit 6), 56 (Visit 7), and weeks 24 (Visit 8), 39 (Visit 9) and 52 (Visit
10). Phone calls will occur on Day 4, 21, and 72. Subject safety and tolerability of the
single dose of MSCs will be evaluated at these study visits by reviewing interval histories,
administering patient questionnaires (legacy [Routine Assessment of Patient Index Data 3
(RAPID 3) / Short Form 36 (SF36)] and Patient Reported Outcome Measurement Information System
(PROMIS) computer adaptive technology CAT), performing physical exams and spirometry, and
obtaining safety laboratories. Special attention will be given to exacerbation of RA or
"flare". This study will also explore the efficacy measures: Disease Activity Score
28-C-Reactive Protein (DAS28-CRP) and American College of Rheumatology20/50/70 (ACR20/50/70
will be calculated. Since the primary hypothesis is that infusion of MSCs will induce a state
of immune tolerance, various assays to detect post-infusion changes in cells subsets,
function or protein biomarker will be repeated at Day 7 and/or 14 and compared to baseline
values (with-in subject comparison). Biomarkers to look at cell-subsets will be drawn.
Selected patient samples will be stored for exploratory studies using Mass Cytometry (Cytof
2). Lastly, for those subjects who are agreeable to undergo the procedure, a bone marrow
aspiration will be performed prior to infusion with allogeneic MSCs. MSCs from RA bone marrow
will be expanded, banked, and used for future translational studies.

Inclusion Criteria:

- 18-80 years

- Recent onset rheumatoid arthritis and have known doctor diagnosis ≤ 1 years and
symptoms for ≤ 2 years.

- Patients must have detectable serum auto-antibodies against cyclic citrullinated
peptides and/or high titer serum rheumatoid factor at screening or prior to screening.

- Subjects must have active synovitis of at least one joint.

- Patients who have been intolerant or had inadequate response to at least twelve weeks
total of methotrexate, ten weeks of which methotrexate must have been dosed at ≥15 mg
per week or with low dose steroids (< 10 mg prednisone per day).

- Clinically stable with no significant changes in health status within 2 weeks prior to
randomization

Exclusion Criteria:

- Prior use of DMARDs other than non-steroidals, low dose prednisone, hydroxychloroquine
and methotrexate

- Use of leflunomide or sulfasalazine for more than 3 days and less than 3 half lives
have passed since discontinuing. For leflunomide, wash out is permissible.

- Prior use of Biologic DMARDs

- Presence of active infection

- History of chronic viral infections including Hepatitis B or C or HIV. Treated
Hepatitis C is allowed if the viral in non-detectable

- Known chronic liver disease

- Pregnant, breastfeeding, or desire to become pregnant or unwilling to practice birth
control during participation in the study and for twelve months after completing the
study infusion, unless surgically sterilized or postmenopausal during the study.

- Active tuberculosis (TB) requiring treatment within 3 years prior to baseline

- Latent TB diagnosed during screening that has not been appropriately treated

- History of Cancer requiring chemotherapy within the past 5 years except Human
Papillomavirus (HPV) related cervical changes that are not carcinoma in situ.

- Chronic obstructive pulmonary disease or known lung disease except for mild asthma
treated with bronchodilators.

- Use of an investigational agent within the 4-week period prior to screen

- If Dimethyl sulfoxide (DMSO) is used in the preparation of MSCs then subjects with
known sensitivity to DMSO will be excluded

- History of Transient Ischemic Attack

- History of Cerebrovascular Accident (stroke)

- Clinically significant heart disease (New York Heart Association, class III and class
IV).