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Multicenter Trial of Stem Cell Therapy for Osteoarthritis (MILES) (MILES)

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ClinicalTrials.gov Identifier: NCT03818737
Recruitment Status : Recruiting
First Posted : January 28, 2019
Last Update Posted : June 10, 2019
Sponsor:
Collaborator:
The Marcus Foundation
Information provided by (Responsible Party):
Scott D Boden, Emory University

Tracking Information
First Submitted Date  ICMJE January 24, 2019
First Posted Date  ICMJE January 28, 2019
Last Update Posted Date June 10, 2019
Actual Study Start Date  ICMJE March 28, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
  • Change in Visual Analog Pain Scale (VAS-pain) scores [ Time Frame: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months ]
    Pain assessment will be done using the VAS-pain scale at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months 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 (mm) on the 10‐cm line between the "no pain" anchor and the participant's mark, providing a range of scores from 0-100. Pain will be assessed at rest and active movement of the affected joint. 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).
  • Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) [ Time Frame: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months ]
    The KOOS questionnaire is an instrument to assess the participant's opinion about their osteoarthritis and associated problems. It consists of 5 subscales; Pain, other Symptoms, Function in daily living (ADL), Function in sport and recreation (Sport/Rec) and knee related Quality of life (QOL). Standardized answer options are given (5 Likert boxes) and each question is assigned a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. A total lower score indicates more problems. The assessment will be done at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03818737 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
  • Change in EuroQuality of Life (EQ5D-3L) scores [ Time Frame: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months ]
    The EQ5D 3L survey measures 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"). The answers to these question are put together to create a 5 digit composite score.This composite score will be indexed to a lookup table which produces a single summary score from 0 to 100. The respondents self-rate their level of severity for each dimension using three levels. The assessment will be done at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months.
  • Change in Patient-Reported Outcomes Measurement Information System (PROMIS 29) scores [ Time Frame: Baseline, 1 month, 3 months, 6 months, 9 months, 12 months ]
    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 will be 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. Higher scores mean more of the specific scale's construct, which may indicate a desirable or an undesirable outcome. The assessment will be done at baseline and at 1 month, 3 months, 6 months, 9 months and at 12 months.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Multicenter Trial of Stem Cell Therapy for Osteoarthritis (MILES)
Official Title  ICMJE 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)
Brief Summary The study is a multicenter trial conducted to compare the effectiveness 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 (UCT) for the treatment of unilateral Knee Osteoarthritis (OA). The study will be conducted in 4 sites in the United States, including Emory University. 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 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 Mesenchymal Stem Cells (MSC's) 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 (MSC's, 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 mesenchymal stem cells 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Prospective, randomized 1:1:1 among 3 arms, multicenter, controlled, single-blinded study anticipating to enroll up to 480 subjects.
Masking: Single (Participant)
Masking Description:
Single-blinded
Primary Purpose: Treatment
Condition  ICMJE Osteoarthritis
Intervention  ICMJE
  • Biological: Autologous Bone Marrow Concentrate (BMAC)
    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.
  • Biological: Adipose-derived Stromal Vascular Fraction (SVF)
    Adipose-derived Stromal Vascular Fraction will be obtained from a mini lipoaspirate. The lipoaspirate will then be enzymatically digested to produce a stromal vascular fraction (SVF) that will be injected into the knee joint. All injections will be made via ultrasound guidance using a standard approach.
  • Biological: Umbilical Cord Tissue (UCT)
    Cryopreserved doses of cord tissue MSCswill be used. These MSCs were cyopreserved 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.
  • Drug: Depomedrol and Normal saline (Corticosteroid injection)
    7cc of the corticosteroid injection 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.
Study Arms  ICMJE
  • Experimental: Autologous BMAC versus corticosteroid
    Forty subjects will be randomized to this arm at each site. They will be further randomized within the arm in a 3:1 ratio to receive either bone marrow derived mesenchymal stem cells (MSCs) or corticosteroid (CS) injection (30:10). All subjects randomized to this arm will undergo bone marrow aspiration, but will only receive one of the injections. At each site, 30 subjects in this arm will receive a standard Orthobiologic injection of Bone Marrow Concentrate (BMAC) and 10 will receive the CS injection. All injections will be made into the knee joint via ultrasound guidance using a standard approach.
    Interventions:
    • Biological: Autologous Bone Marrow Concentrate (BMAC)
    • Drug: Depomedrol and Normal saline (Corticosteroid injection)
  • Experimental: Adipose-derived SVF versus corticosteroid
    Forty subjects will be randomized to this arm at each site. They will be further randomized within the arm in a 3:1 ratio to receive either an injection of Adipose-derived Stromal Vascular Fraction (SVF) or corticosteroid (CS) (30:10). All subjects randomized to this arm will undergo small volume lipoplasty, but will only receive one of the injections. At each site, 30 subjects in this arm will receive the Adipose-derived Stromal Vascular Fraction (SVF) and 10 subjects will receive the CS injection. All injections will be made into the knee joint via ultrasound guidance using a standard approach.
    Interventions:
    • Biological: Adipose-derived Stromal Vascular Fraction (SVF)
    • Drug: Depomedrol and Normal saline (Corticosteroid injection)
  • Experimental: Umbilical Cord Tissue (UCT) versus corticosteroid
    Forty subjects will be randomized to this arm at each site. They will be further randomized within the arm in a 3:1 ratio to receive either an injection of cryopreserved doses of cord tissue MSCs or corticosteroid (30:10) injected into the knee. At each site, 30 subjects in this arm will receive the umbilical cord tissue MSCs and 10 subjects will receive the CS injection. All injections will be made into the knee joint via ultrasound guidance using a standard approach.
    Interventions:
    • Biological: Umbilical Cord Tissue (UCT)
    • Drug: Depomedrol and Normal saline (Corticosteroid injection)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2019)
480
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age >40 but <70 years old
  • Males and females
  • Recent knee radiograph of the targeted knee (standing 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 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 ≤ 7 days 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 (+/- 5 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 OHRP definition (pregnant women and breast-feeding women, cognitively impaired, prisoners, etc.)
  • Use of NSAIDS within 1 week of 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
  • If deemed medically inappropriate or noncompliant by the treating investigator
  • Uncontrolled diabetes
  • Subject has an active workers' compensation case in progress
  • Subject with insufficient amount of subcutaneous tissue to allow recovery of a minimum of 100 mL of lipoaspirate
  • 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 and 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kenneth Mautner, MD 404-778-7142 aakard@emory.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03818737
Other Study ID Numbers  ICMJE IRB00108046
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description:
  1. Will individual de-identified participant data be shared? No.
  2. What data in particular will be shared? Not Applicable.
  3. What related documents will be available? Not Applicable.
  4. When will data become available (start & end date)? Not Applicable.
  5. By what access criteria will data be shared: Not Applicable.
Responsible Party Scott D Boden, Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE The Marcus Foundation
Investigators  ICMJE
Study Director: Hicham Drissi, PhD Emory University
Principal Investigator: Scott D Boden, MD Emory University
PRS Account Emory University
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP