Multicenter Trial of Stem Cell Therapy for Osteoarthritis (MILES)

NCT ID: NCT03818737

Last Updated: 2023-07-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 475 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-28
• Study Completion Date: 2022-05-31

Brief Summary

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.

Detailed Description

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.

Conditions

Osteoarthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Bone Marrow Derived MSCs

Participants randomized to this arm will undergo bone marrow aspiration and then will be further randomized to receive a standard orthobiologic injection into the knee joint of autologous bone marrow concentrate (BMAC).

Group Type: EXPERIMENTAL

Bone Marrow Derived MSCs

Intervention Type: BIOLOGICAL

Autologous bone marrow concentrate (BMAC) is a standard orthobiologic injection for knee osteoarthritis. The procedure involves harvesting of bone marrow aspirate (BMA) from the posterior superior iliac spine (PSIS) and then following centrifugation in an FDA approved device (EmCyte GenesisCS Pure BMAC®-60 ml) will be injected back into the knee joint. All injections will be made via ultrasound guidance using a standard approach.

Adipose-derived MSCs

Participants randomized to this arm will undergo small volume lipoplasty, and then will be further randomized to receive an injection into the knee joint of adipose-derived stromal vascular fraction (SVF).

Group Type: EXPERIMENTAL

Adipose-derived MSCs

Intervention Type: BIOLOGICAL

Adipose-derived Stromal Vascular Fraction (SVF) will be obtained from a mini lipoaspirate. The lipoaspirate will then be enzymatically digested to produce a SVF that will be injected into the knee joint. All injections will be made via ultrasound guidance using a standard approach.

Umbilical Cord Tissue (UCT) MSCs

Participants randomized to this arm will receive an injection into the knee joint of cryopreserved doses of umbilical cord tissue MSCs.

Group Type: EXPERIMENTAL

Umbilical Cord Tissue (UCT) MSCs

Intervention Type: BIOLOGICAL

Cryopreserved doses of umbilical cord tissue MSCs will be used. These MSCs were cryopreserved at P2 culture in plasmalyte A + 5% human serum albumin in 5 finger cryobags containing 20 million cells in 4 mL and stored under liquid nitrogen until shipment. Cells will be transported in a dry shipper and thawed at the study sites. The dose of MSCs will be aspirated from the cryobag into a sterile syringe and directly injected into the knee. All injections will be made via ultrasound guidance using a standard approach.

Corticosteroid Injection

Participants randomized to the bone marrow derived MSC, adipose-derived MSC, or umbilical cord tissue MSC study arms will be further randomized within the arm in a 3:1 ratio to receive either MSCs derived from the study arm of the initial randomization or a corticosteroid (CS) injection. Participants randomized to the control group will receive an injection of corticosteroid into the knee joint.

Group Type: ACTIVE_COMPARATOR

Corticosteroid injection

Intervention Type: DRUG

The corticosteroid injection is prepared by mixing 1cc of 40mg/dL depomedrol and 6cc of normal saline in a 10cc syringe will be made into the knee joint. All injections will be made via ultrasound guidance using a standard approach.

Interventions

Bone Marrow Derived MSCs

Autologous bone marrow concentrate (BMAC) is a standard orthobiologic injection for knee osteoarthritis. The procedure involves harvesting of bone marrow aspirate (BMA) from the posterior superior iliac spine (PSIS) and then following centrifugation in an FDA approved device (EmCyte GenesisCS Pure BMAC®-60 ml) will be injected back into the knee joint. All injections will be made via ultrasound guidance using a standard approach.

Intervention Type: BIOLOGICAL

Adipose-derived MSCs

Adipose-derived Stromal Vascular Fraction (SVF) will be obtained from a mini lipoaspirate. The lipoaspirate will then be enzymatically digested to produce a SVF that will be injected into the knee joint. All injections will be made via ultrasound guidance using a standard approach.

Intervention Type: BIOLOGICAL

Umbilical Cord Tissue (UCT) MSCs

Cryopreserved doses of umbilical cord tissue MSCs will be used. These MSCs were cryopreserved at P2 culture in plasmalyte A + 5% human serum albumin in 5 finger cryobags containing 20 million cells in 4 mL and stored under liquid nitrogen until shipment. Cells will be transported in a dry shipper and thawed at the study sites. The dose of MSCs will be aspirated from the cryobag into a sterile syringe and directly injected into the knee. All injections will be made via ultrasound guidance using a standard approach.

Intervention Type: BIOLOGICAL

Corticosteroid injection

The corticosteroid injection is prepared by mixing 1cc of 40mg/dL depomedrol and 6cc of normal saline in a 10cc syringe will be made into the knee joint. All injections will be made via ultrasound guidance using a standard approach.

Intervention Type: DRUG

Other Intervention Names

Depo-Medrol; Methylprednisolone

Eligibility Criteria

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

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Marcus Foundation

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: lead

Responsible Party

Scott D Boden

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hicham Drissi, PhD

Role: STUDY_DIRECTOR

Emory University

Scott D Boden, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Andrews Institute

Gulf Breeze, Florida, United States

The Emory Clinic

Atlanta, Georgia, United States

Duke University

Durham, North Carolina, United States

Sanford Health

Fargo, North Dakota, United States

Sanford Health

Sioux Falls, South Dakota, United States

Countries

United States

References

Mautner K, Kaiser JM, Boggess B, Hackel J, Kurtenbach C, Noonan B, Shenvi N, Easley KA, Myer GD, Jayaram P, Gottschalk M, Boden S, Drissi H. Autologous Cell Injections for Knee Osteoarthritis Display Greater Responsiveness Than Allogenic Cellular Products and Corticosteroids in a Sex-Dependent Manner. Am J Sports Med. 2025 Oct;53(12):2889-2897. doi: 10.1177/03635465251365521. Epub 2025 Sep 27.

Reference Type: DERIVED

PMID: 41014273 (View on PubMed)

Mautner K, Gottschalk M, Boden SD, Akard A, Bae WC, Black L, Boggess B, Chatterjee P, Chung CB, Easley KA, Gibson G, Hackel J, Jensen K, Kippner L, Kurtenbach C, Kurtzberg J, Mason RA, Noonan B, Roy K, Valentine V, Yeago C, Drissi H. Cell-based versus corticosteroid injections for knee pain in osteoarthritis: a randomized phase 3 trial. Nat Med. 2023 Dec;29(12):3120-3126. doi: 10.1038/s41591-023-02632-w. Epub 2023 Nov 2.

Reference Type: DERIVED

PMID: 37919438 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB00108046

Identifier Type: -

Identifier Source: org_study_id