Mesenchymal Stem Cells in Early Rheumatoid Arthritis

Cell-Based Therapy in Rheumatoid Arthritis: Proof of Concept Phase 1 Trial

This is a prospective, multicenter, double-blind, placebo controlled interventional study to evaluate the safety and efficacy of allogeneic mesenchymal stem cells (MSCs) in 20 patients with new onset Rheumatoid Arthritis (RA). The study is a single dose, phase I clinical trial and is the first time that this product will be infused in RA patients. The study duration is approximately fourteen months from time of screening to completion.

Research hypothesis: The investigators hypothesize that when administered therapeutically, MSCs will induce healthy immune responses and will reduce RA disease activity. This study is primarily focused on demonstrating the safety of this approach.

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Biological: 2 million hMSC/kg; Biological: placebo; Biological: 4 million hMSC/kg; Biological: 6 million hMSC/kg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Nora Singer, MD; Phone Number: 216-778-2323; Email: nsinger@metrohealth.org
• Study Contact Backup: Name: Larraine Gordesky, MS, RN, BSN; Phone Number: 216-778-8927; Email: lgordesky1@metrohealth.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44106
      • UH Hospitals Cleveland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18-80 years
• Recent onset rheumatoid arthritis and have known doctor diagnosis ≤ 2 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), unless there has been no CVA for > or = 1 year after the resolution of the underlying cause of the CVA
• Clinically significant heart disease (New York Heart Association, class III and class IV).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; 2 million human MSC (hMSC)/kg infusion versus placebo infusion	Biological: 2 million hMSC/kg; 2 million hMSCs/kg infusion; Biological: placebo; placebo infusion
Experimental: Cohort 2; 4 million hMSC/kg infusion versus placebo infusion	Biological: placebo; placebo infusion; Biological: 4 million hMSC/kg; 4 million hMSC/kg infusion
Experimental: Cohort 3; 6 million hMSC/kg infusion versus placebo infusion	Biological: placebo; placebo infusion; Biological: 6 million hMSC/kg; 6 million hMSC/kg infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety assessed by dose limiting toxicity (DLT)	• In addition, a DLT will be assigned if through 14 days after the infusion any grade 3-4 adverse event for pulmonary, cardiac, renal, oral mucosal or hepatic, and grade 4 adverse events for other organs occurred per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.	14 days following infusion
Safety assessed by dose limiting toxicity	• A DLT is triggered by occurrence through 48 hours after infusion of grade ≥2 infusion-related allergic toxicities, which include rash, flushing, urticaria, dyspnea, fever ≥38°C (≥100.4°F) as scored according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) version 4.03.	48 hours following infusion
Safety assessed by change in spirometry	• Changes in spirometry following infusion compared to baseline	30 minutes following infusion
Safety assessed by all adverse events	• Incidence and severity of adverse events	52 weeks following infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in patient reported outcomes	2. Change in patient reported outcomes (PROMIS CAT and legacy [RAPID 3 / SF36] -questionnaires)	Up to day 28 after infusion
DAS28-CRP	Changes in DAS28-CRP	Week 52

Collaborators and Investigators

• Sponsor: MetroHealth Medical Center
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Nora singer, MD, MetroHealth Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2017
• Primary Completion (Actual): April 30, 2023
• Study Completion (Actual): May 31, 2023

Study Registration Dates

• First Submitted: June 12, 2017
• First Submitted That Met QC Criteria: June 12, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): June 23, 2023
• Last Update Submitted That Met QC Criteria: June 22, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Arthritis, Rheumatoid, Stem Cells, Mesenchymal, Autoimmune
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: IRB16-00587; R21AR069226 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No