Multicenter Trial of Stem Cell Therapy for Osteoarthritis (MILES)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Osteoarthritis

Intervention / Treatment
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* Biological: Bone Marrow Derived MSCs
* Biological: Adipose-derived MSCs
* Biological: Umbilical Cord Tissue (UCT) MSCs
* Drug: Corticosteroid injection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will include a parallel design using a blocked central randomization scheme of 1:1:1:1. Participants will first be randomized to have MSCs derived from either bone marrow, adipose tissue, or umbilical cord tissue. Then they will be further randomized to receive either an injection of MSCs (from bone marrow, adipose, or umbilical cord tissue, depending on the first randomization) or a corticosteroid injection.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bone Marrow Derived MSCs<br>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). | Biological: Bone Marrow Derived MSCs<br>* 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.<br>|
| Experimental: Adipose-derived MSCs<br>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). | Biological: Adipose-derived MSCs<br>* 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.<br>|
| Experimental: Umbilical Cord Tissue (UCT) MSCs<br>Participants randomized to this arm will receive an injection into the knee joint of cryopreserved doses of umbilical cord tissue MSCs. | Biological: Umbilical Cord Tissue (UCT) MSCs<br>* 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.<br>|
| Active Comparator: Corticosteroid Injection<br>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. | Drug: Corticosteroid injection<br>* 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.<br>* Other names: Methylprednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Visual Analog Pain Scale (VAS-pain) Score | Pain assessment was performed using the Visual Analog Pain Scale (VAS-pain). The VAS-pain is self-completed by the participant. The respondent is asked to place a line perpendicular to the VAS line at the point that represents their pain intensity. Using a ruler, the score is determined by measuring the distance in millimeters (mm) on the line between the no pain anchor and the participant's mark, providing a range of scores from 0-100. The recommended cut points for VAS are: no pain (0-4 mm), mild pain (5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm). The change in VAS-pain score is the score from the each follow-up visit subtracted from the baseline score. A negative value means that pain has reduced from what it was at baseline. | Baseline, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) - Pain Subscale Score | The KOOS questionnaire assesses the participant's opinion about their osteoarthritis and associated problems. It consists of 5 subscales: pain, symptoms, activities of daily living (ADL) function, sport and recreation function, and knee related quality of life (QoL). The pain subscale has 9 items and response options are given on a 5-point Likert scale where 0 = no problems and 4 = extreme problems. Scores are transformed to a scale ranging from 0 to 100 with 0 indicating extreme symptoms and 100 indicating no symptoms. The change in KOOS-pain subscale score is the score from each follow-up visit subtracted from the baseline score. A negative value means that pain has worsened from what it was at baseline, while a positive value means that pain has improved from baseline. | Baseline, 1 month, 3 months, 6 months, 9 months, 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) - Total Score | The KOOS questionnaire assesses the participant's opinion about their osteoarthritis and associated problems. It consists of 5 subscales: pain, symptoms, activities of daily living (ADL) function, sport and recreation function, and knee related quality of life (QoL). The KOOS has 42 items across all subscales and response options are given on a 5-point Likert scale where 0 = no problems and 4 = extreme problems. The sum of subscale scores is transformed to a scale ranging from 0 to 100 with 0 indicating extreme symptoms and 100 indicating no symptoms. A negative value means that pain has worsened from what it was at baseline, while a positive value means that pain has improved from baseline. | Baseline, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Change in EuroQuality of Life (EQ-5D-3L) Index Score | The EQ-5D-3L survey measures the severity of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The participants will be asked to answer questions regarding these measures and to indicate their current experience on a scale from 1 to 3 (1 being no problem and 3 being most extreme problem). A sixth item asks participants to rate their current heath from 0 (worst imaginable) to 100 (best imaginable). The answers to these questions are converted into an index value based on the country respondents live in. Health state index scores typically range from less than 0 to 1, where 0 is a health state equivalent to death and 1 is perfect health. Positive values for the change from baseline score indicate improved health. | Baseline, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Patient-Reported Outcomes Measurement Information System (PROMIS-29) Score | The PROMIS-29 assesses seven health domains: physical function, anxiety, depression, fatigue, sleep disturbance, pain interference, and ability to participate in social roles and activities. Each of the seven domains has four questions which are scored on a five-point Likert scale. The PROMIS-29 scales are scored using a T-score metric method available at the Assessment Center website (http://assessmentcenter.net). A score of 50 points represents the population average for each scale, and 10 points represent one standard deviation. Scores higher than 50 indicate more of the specific scale's construct, which may indicate a desirable or an undesirable outcome. | Baseline, 1 month, 3 months, 6 months, 9 months, 12 months | 
| Overall MRI Grade of Osteoarthritis | An MRI grade of osteoarthritis was calculated by rating features viewed by MRI (such as cartilage loss) in terms of severity and extent. Total scores range from 0 to 69 with higher values indicating more severe osteoarthritis. | Baseline, Month 6, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mesenchymal stem cells, corticosteroids, bone marrow aspiration, adipose-derived stromal vascular fraction