Clinical trial NCT05517434: Autologous BMA vs Saline and LAM + LP-PRP vs Saline Evaluations in Knee OA
Official title: Intra-Articular Autologous Bone Marrow Aspirate vs Placebo Injection and Lipoaspirate Micronized With Leukocyte-Poor Platelet Rich Plasma vs Placebo Injection Evaluations for Treatment of Knee OsteoArthritis: The ABLE OA Double-Blinded Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Osteoarthritis, Knee
Keywords: placebo
intra-articular injection
autologous therapy
bone marrow aspirate
lipoaspirate
platelet-rich plasma
leukocyte-poor
pain
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Women's College Hospital
First posted: 2022-08-26
Enrollment: 148
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: STUDY 1 (N=74): All patients will undergo a bone marrow aspiration. A BMA injection \[Arm A, n=37\] will be compared to a saline injection \[Arm C, n=37\].

STUDY 2 (N=74): All patients will undergo a blood collection and lipoaspiration. A LAM injection followed by LP-PRP injection \[Arm B, n=37\] will be compared to two consecutive saline injections \[Arm D, n=37\].
Primary purpose: TREATMENT

Brief summary: ABLE OA is a Health Canada authorized (phase II/III) trial \[Parent Control #: 263591\]. A multi-center, prospective, double-blinded, randomized, placebo-controlled adaptive trial to evaluate the efficacy of two minimally manipulated autologous cellular preparations i) bone marrow aspirate (BMA) injection; and, ii) combined lipoaspirate micronized (LAM) and leukocyte poor (LP) platelet-rich plasma (PRP) injections for the treatment of knee osteoarthritis (OA).

BMA, LAM from lipoaspirate (LA), and LP-PRP from whole blood will be prepared using the Cervos Marrow Cellution™ Bone Marrow Aspiration System, Cervos LIPO-PRO™ Adipose Transfer System, and Cervos KEYPRP Platelet Separator System, respectively.

Patient-reported outcome (PRO) measures will be collected using web- or paper-based questionnaires administered at baseline (pre-injection) as well as at 3, 6 and 12 months (post-injection). Blood, synovial fluid, and urine samples will be collected at baseline pre-injection and 6 months post-injection only.

Detailed description: Trial interventions will occur in two independent studies under a single protocol where each experimental treatment will be compared to a placebo control.

Our primary hypothesis is that BMA or LAM + LP-PRP injection is 35% more effective than placebo saline injection control in terms of response rates in Numeric Pain Rating Scale (NPRS) scores as measured by their difference.

PRIMARY OBJECTIVE:

To determine the efficacy of an intra-articular injection of BMA or LAM + LP-PRP in patients with knee OA by comparing each of the two treatments to a placebo saline injection control arm. Efficacy will be measured by a pain intensity improvement of a minimum of 2 points in NPRS scores at 6 months after injection relative to baseline. The study endpoint is 6 months post-injection.

KEY SECONDARY OBJECTIVE:

To determine efficacy measured by improvements in the Knee Injury and Osteoarthritis Outcome Score (KOOS) function activities of daily living (ADL) subscale scores at 6 months after injection relative to baseline by comparing each of the treatment (BMA or LAM + LP-PRP) arm to a placebo saline control arm.

OTHER SECONDARY OBJECTIVES:

* To evaluate if an injection of BMA or LAM + LP-PRP into the knee joint shows greater improvements in other pain outcomes (including KOOS pain) compared to placebo injection at 3, 6 and 12 months post-injection relative to baseline.
* To evaluate the safety of BMA or LAM + LP-PRP injection into the knee joint compared to placebo injection. Adverse events will be collected at baseline, 3, 6 and 12 months post-injection, and deleterious effects on the joint will be assessed by X-ray at 6 months post-injection only.
* To evaluate the health profile and overall self-rated health status of patients in treatment and placebo arms at 3, 6 and 12 months post-injection relative to baseline.
* To evaluate overall patient satisfaction in treatment and placebo arms at 6 months post-injection.

EXPLORATORY OBJECTIVES:

To determine the correlation between changes in NPRS/KOOS pain scores and KOOS ADL function at 6 months relative to baseline and the heterogeneity in:

1. the cellular composition and soluble factors in BMA, LAM and LP-PRP autologous cellular preparations \[in BMA or LAM + LP-PRP groups only\]
2. the levels of local and systemic immune cell and inflammatory profiles of patients (based on synovial fluid, blood, and urine readouts) \[in BMA or LAM + LP-PRP and placebo groups\]

A total of approximately 84 eligible participants in each study will be randomized in a 1:1 ratio, which allows for 42 participants per group (treatment vs. placebo). This sample size considers a potential drop-out rate of 10% for each study. Three recruitment centres (Toronto Western Hospital (TWH), University Health Network (UHN); Women's College Hospital (WCH); Cleveland Clinic Canada (CCC)) and one treatment centre (TWH, UHN) will be involved in these two studies. Stratification will occur by centre, baseline NPRS of 4-6 (moderate pain) or 7-10 (severe pain), and KL grade of 2 (minimal OA) or 3 (moderate OA). Additionally, the need to re-estimate the required sample size will be evaluated using the information available at interim. At the interim analysis, contingent on observed response rates and corresponding statistical signal, the required sample size may increase, ranging from 100 to 288 patients in total for each of the two studies.

Eligibility criteria: Inclusion Criteria:

* Male or female at least 30 years of age at the time of screening
* Willingness and ability to comply with study procedures and visit schedules and able to follow oral and written instructions
* Signed consent for study participation
* Baseline NPRS ≥ 4 points
* Unilateral, symptomatic, chronic knee pain
* KL grade 2 or 3 knee OA based on standing knee X-ray assessment
* Body mass index ≤ 30 kg/m2

Exclusion Criteria:

* Approved anti-inflammatory therapy injections (corticosteroid, Synvisc, PRP, nSTRIDE-Autologous Protein Solution) within the previous 6 months in the knee
* Major axial deviation (varus \>10°, valgus \>10°)
* Any concomitant knee lesion causing pain or effusion (i.e., ligamentous or meniscal injury, osteochondral lesion)
* Presence of clinically observed active infection in the index knee
* Diagnosed with rheumatoid arthritis, Reiter's syndrome, psoriatic arthritis, gout, ankylosing spondylitis, or arthritis secondary to other inflammatory diseases; chondrocalcinosis, Paget's disease, or villonodular synovitis
* Diagnosed with leukemia or other hematologic cancers, known presence of metastatic malignant cells, or ongoing or planned chemotherapeutic treatment
* Presence of venous or lymphatic stasis in the index leg
* A history of local anesthetic allergy
* Medical conditions such as hemophilia or other blood clotting disorders
* Arthroscopic knee surgery within the previous 6 months
* Daily opioid use for the past 3 months, use of non-steroidal anti-inflammatory drugs within 1 week of the procedure, unable to hold anti-platelet medications
* Use of systemic corticosteroids for treatment of a chronic medical condition within the past 3 months
* Immunosuppression or acute infective processes

Study Treatment Eligibility:

* For Study 1: Inability to tolerate the bone marrow aspiration procedure resulting in insufficient collection of BMA (\<10 mL) after two successive aspiration attempts
* For Study 2: Inability to tolerate the lipoaspiration procedure resulting in insufficient collection of LA (\<40 mL) after two successive aspiration attempts

Primary outcomes:
measure: Pain Level Changes. Differences in response rates between groups (treatments vs placebos) at 6-months (end of study) compared to baseline. Response is based on an improvement of 2 units or more in the Numeric Pain Rating Scale (NPRS).
timeFrame: baseline (pre-injection) and 3, 6 and 12 months (post-injection)
Secondary outcomes:
measure: Functional Changes. Differences in mean change of Knee Injury and Osteoarthritis Outcome Score (KOOS) Activities of Daily Living (ADL) subscale scores between groups (treatments vs placebos) at 6-months (end of study) compared to baseline.
timeFrame: baseline (pre-injection) and 3, 6 and 12 months (post-injection)
measure: Additional Pain Level Changes. Mean NPRS subscale change score at 6 months relative to baseline in treatment groups compared to placebo groups.
timeFrame: baseline (pre-injection) and 3, 6 and 12 months (post-injection)
measure: Additional Pain Level Changes. Mean KOOS pain subscale change score at 6 months relative to baseline in treatment groups compared to placebo groups.
timeFrame: baseline (pre-injection) and 3, 6 and 12 months (post-injection)
measure: Health-Related Quality of Life Changes. Mean utility and EuroQol-Visual Analogue Scale (EQ-VAS) change scores at 6 months (end of study) relative to baseline in treatment groups compared to placebo groups.
timeFrame: baseline (pre-injection) and 3, 6 and 12 months (post-injection)
measure: Safety. Proportion of cumulative adverse events (AEs) at 6 months post-injection in treatment groups compared to placebo groups.
timeFrame: baseline (pre-injection) and 3, 6 and 12 months (post-injection)
measure: Treatment Satisfaction. Percent satisfaction at 6 months in treatment groups compared to placebo groups.
timeFrame: 6 months (post-injection)
Other outcomes:
measure: Total nucleated cell count (TNC) in the BMA and LAM cellular preparations in treatment groups only.
timeFrame: baseline (pre-injection) and 6 months (post-injection)
measure: Percentages of hematopoietic, endothelial, and stromal cells in the BMA and LAM cellular preparations in treatment groups only.
timeFrame: baseline (pre-injection) and 6 months (post-injection)
measure: Levels of soluble/secreted factors (FGF2, G-CSF, IL-1RA/IL-1F3, IL-4, IL-10, PDGF-BB, VEGF) in the BMA, LAM and LP-PRP cellular preparations in treatment groups only.
timeFrame: baseline (pre-injection) and 6 months (post-injection)
measure: Local and systemic levels of immune cells and inflammatory cytokines and chemokines in synovial fluid and blood in treatment groups and placebo groups.
timeFrame: baseline (pre-injection) and 6 months (post-injection)
measure: Systemic levels of inflammatory and catabolic factors in synovial fluid, blood and urine in treatment groups and placebo groups.
timeFrame: baseline (pre-injection) and 6 months (post-injection)
Locations:
city: Toronto
country: Canada
facility: Women's College Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital, University Health Network
state: Ontario
Study officials:
affiliation: University Health Network, Toronto
name: Sowmya Viswanathan, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Christian Veillette, MD, MSc, FRCSC
role: STUDY_DIRECTOR
affiliation: University Health Network, Toronto
name: Christopher Kim, HBSc, MSc, MD, FRCSC, PhD(c)
role: PRINCIPAL_INVESTIGATOR
References: