Multicenter Trial of Stem Cell Therapy for Osteoarthritis (MILES)

Randomized Multicenter Phase 3 Single-blind Trial Comparing the Efficacy of Corticosteroid Control to Mesenchymal Stem Cell Preparations From Autologous Bone Marrow Concentrate (BMAC), Adipose-derived Stem Cells in the Form of Stromal Vascular Fraction (SVF), and Third-party Human Mesenchymal Stem Cells Manufactured From Umbilical Cord Tissue for the Treatment of Unilateral Knee Osteoarthritis (OA)

The study is a multicenter trial conducted to compare the effectiveness of an injection of a corticosteroid control to mesenchymal stem cell (MSC) preparations from autologous bone marrow concentrate (BMAC), adipose derived stem cells in the form of Stromal Vascular Fraction (SVF), and third-party human mesenchymal stem cells manufactured from umbilical cord tissue (UCT) for the treatment of unilateral Knee Osteoarthritis (OA). The study will be conducted in 4 sites in the United States, and a total of 480 participants will be enrolled in this study.

Primary osteoarthritis is a debilitating disease characterized by extensive damage to the joints and excruciating pain leading to loss of activity and depression. Despite advances in diagnosis and relatively efficient control of nociception, to date, the quest for the development of a disease modifying osteoarthritis drug has proven unsuccessful. The potential of mesenchymal stem cells (MSCs) to inhibit inflammation while promoting healing makes them amenable for the treatment of various ailments ranging from cancer to genetic diseases. In orthopedic practice, autologous stem cell injections are performed to alleviate the pain associated with osteoarthritis. A serious gap in knowledge remains whether the currently used cellular treatments are beneficial in the long term and if one cell therapy outperforms another.

The most popular form of autologous MSC therapy has been through the use of autologous bone marrow concentrate (BMAC). The rationale is that when a sample of bone marrow aspirate (BMA) is collected and the components that are not beneficial to the joint are filtered out (i.e. red blood cells, neutrophils, etc.) the remaining concentrate (MSCs, platelets, interleukins, etc) can have a "healing" effect on the environment in which it is injected. However it is still unknown as to how effective BMAC is for treating orthopedic conditions compared to other MSC procedures and the most important components of the BMAC mixture that could aid patients suffering from osteoarthritis.

Adipose tissue has been found to have a large amount of MSCs versus that in bone marrow. These cells are currently being used in a variety of clinical research studies within the regenerative medicine field. Through a tissue process which includes washing and centrifuging, the cellular components can be extracted as a cell pellet, which is also known as stromal vascular fraction (SVF). Adipose derived SVF is obtained via liposuction, or the removal of adipose tissue via a suction method.

Although the use of various stem cell preparations for knee osteoarthritis has become increasingly prevalent, well-designed studies with conclusive proof of comparative effectiveness and identification of the optimal cell source and "dose" have not been performed. This study is the first randomized study comparing three types of cellular treatments to corticosteroids. The main objective of the study is to identify a superior source of stem cells for the treatment of osteoarthritis and validate its advantages over corticosteroid injections as the traditional gold standard treatment.

Participants will be randomized study arms with different types of MSCs (bone marrow derived MSC, adipose derived MSC, and umbilical cord tissue MSC) and then will be further randomized to receive an injection of the MSC type they were initially assigned to or corticosteroid. Participants randomized to bone marrow derived MSC or adipose derived MSC will undergo a procedure (bone marrow aspiration or liposuction). Participants will be blinded to whether they receive the MSC or corticosteroid injection.

Inclusion Criteria:

• Age greater or equal to 40 but less than or equal to 70 years old
• Males and females
• Recent knee radiograph of the targeted knee (standing anteroposterior (AP) lateral and sunrise view)
• Diagnosis of OA in the targeted knee (radiographic evidence of OA in the medial and/or lateral tibiofemoral compartment, which would include one or more osteophytes on a standard radiograph taken within 3 months)
• Continued OA pain in the targeted knee despite conservative measures (per treating provider's discretion)
• Average daily Visual Analog Scale (VAS) ≥3
• Kellgren-Lawrence system of Grade II, III, or IV
• Subjects may have concomitant patellofemoral but they must have stage II or higher generalized knee OA
• Females of childbearing potential only, must have a negative pregnancy test done at screening prior to enrollment in the study
• Women and men of child-producing potential must agree to use acceptable contraception methods for the duration of the trial such as birth control pills or condoms with spermicide

Exclusion Criteria:

• Clinically apparent tense effusion of the targeted knee
• Significant valgus/varus deformities (+/- 10 degrees)
• Viscosupplementation within 6 months in the targeted knee
• Other biologic injection (PRP or stem cell) within 1 year in the targeted knee
• Surgery in the targeted knee within the past 6 months (either open or scope)
• Systemic or intra-articular injection of corticosteroids in any joint within 3 months before screening
• Daily opioid use for the past three months
• History of malignancy in the previous 5 years prior to study entry, with the exception of in-situ cancers treated only by local excision with curative intent
• History of, or ongoing, autoimmune disorder that requires treatment with an immunosuppressive medication
• Active, suspected, or prior infection to the joint in the targeted knee
• Part of a vulnerable population per Office for Human Research Protections (OHRP) definition (pregnant women and breast-feeding women, cognitively impaired, prisoners, etc.)
• Unwilling to discontinue the use of Non-Steroidal Anti-Inflammatory (NSAID)s for 7 calendar days prior to the procedure
• Unwilling to discontinue use of NSAIDS for 5 calendar days after procedure
• History of bleeding disorders or inflammatory joint disease
• Inability to hold anti-platelet therapy according to treating provider prior to procedure
• Subject is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason
• Uncontrolled diabetes
• Subject has an active workers' compensation case in progress with targeted knee
• Subject with insufficient amount of subcutaneous tissue
• Hemoglobin less than 10g/dL at the time of screening
• Leukocytes <3,000/μL; neutrophils <1,500/μL; lymphocytes <800/μL; platelets <100,000/μL at the time of screening
• Diagnosis of liver disease as defined by alanine aminotransferase (ALT) >3x the upper limit of age-determined normal (ULN) or total bilirubin > 1.5x ULN
• Subjects who have had greater than 3 corticosteroid injections in the targeted knee in the 12 months prior to screening or at the physician's discretion
• Subjects with a known diagnosis of osteoporosis
• Subjects with anticipated use of systemic corticosteroids during the study period for treatment of a chronic medical condition