Prospective Evaluation of PRP and BMC Treatment to Accelerate Healing After ACL Reconstruction

Prospective Evaluation of Platelet-Rich Plasma and Bone Marrow Concentrate Treatment to Accelerate Healing After Anterior Cruciate Ligament Reconstruction

This is a prospective, randomized, placebo-controlled trial to evaluate potential beneficial effects of leukocyte-poor platelet rich plasma and bone marrow concentrate on the healing and health of critical joint tissues in the knee following anterior cruciate ligament (ACL) reconstruction. Bone marrow contains stem cells which can change into cells of various different tissue types, while platelet rich plasma contains growth factors. This trial will compare the two procedures against placebo.

Study Overview

• Status: Recruiting
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Biological: Leukocyte-Poor Platelet Rich Plasma (LP-PRP); Biological: Bone Marrow Concentrate (BMC); Other: Control group (Placebo)

Detailed Description

This is a prospective, randomized, placebo-controlled trial. Patients will be randomized into three groups: Concentrated Bone Marrow Concentrate (BMC), Platelet-Rich Plasma (PRP) or Placebo. BMC subjects will have bone marrow aspirated from the subjects iliac crests and the cellular rich portion will be concentrated and subsequently injected into the subjects' symptomatic knee during ACL reconstruction surgery. PRP subjects will have a venous blood draw and the resulting PRP will be injected into the symptomatic knee during ACL reconstruction surgery. Follow-up visits in person will take place at 2 weeks, 6 months and 12 months after the ACL reconstruction surgery.

The purpose of this study is to evaluate potential beneficial effects of leukocyte-poor platelet-rich plasma (LP-PRP) and bone marrow concentrate (BMC) on the healing and health of all critical joint tissues (grafts/ligaments, meniscus and cartilage) in the knee following anterior cruciate ligament reconstruction (ACLR). Key aspects of this proposal include our well-developed methodologies to quantify and correlate cytokines, chemokines, growth factors in PRP and progenitor cells in BMC, clinical outcomes and imaging following ACLR. The overarching goal of this randomized control trial is to establish a biological signature of PRP and BMC that will be indicative for optimal recovery after ACLR. The long-term goal of our research is to better understand the efficacy of orthobiologic approaches to improve clinical outcomes, enhance graft healing and mitigate post-traumatic osteoarthritis (PTOA) in a cohort of patients that have undergone ACLR.

• Study Type: Interventional
• Enrollment (Anticipated): 99
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Suzanne L Page, JD; Phone Number: 970-401-8770; Email: spage@sprivail.org

Study Locations

• United States
  • Colorado
    • Vail, Colorado, United States, 81657-5242
      • Recruiting
      • 181 West Meadow Drive, Suite 1000
      • Contact: Suzanne L Page, JD; Phone Number: 970-401-8770; Email: spage@sprivail.org
      • Sub-Investigator: Armando Vidal, MD
      • Sub-Investigator: Jon Godin, MD
      • Principal Investigator: Peter Millett, MD
      • Sub-Investigator: Matthew Provencher, MD
      • Sub-Investigator: Thomas Hackett, MD
      • Sub-Investigator: Leslie Vidal, MD
      • Sub-Investigator: Thomas Evans, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 48 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria: Subjects will be included if all the following criteria are met:

1. Age 16-50 years at the time of Anterior Cruciate Ligament Reconstruction (ACLR) surgery;
2. Acute ACL injury within 6 months of scheduled ACLR surgery;
3. Scheduled for unilateral, primary ACLR with a BTB (bone-patellar tendon-bone) autograft;

4. The following concomitant injuries are allowed:

   1. Meniscal injuries of all types, grades and regardless of surgical treatment;
   2. Articular chondral injury that can be addressed with debridement or chondroplasty;
   3. Tibial impaction fractures;
   4. Non-operative sprains/injuries of MCL or LCL;
5. Willing and able to comply with all required post-operative visits, biomotion and imaging tests, the self-completion of questionnaires and other trial procedures.

Exclusion Criteria: Subjects will be excluded if any of the following criteria are met:

1. Inability to provide informed consent;
2. Women who are pregnant;
3. Previous surgery for either knee except in cases of prior diagnostic arthroscopy and/or minimal debridement;
4. Significant osteoarthritis (OA) of the knee (e.g. grade 4 with cystic changes and/or significant osteophytes);
5. Concomitant cartilage restoration procedure in the operative knee;
6. Biologic treatment (e.g. PRP, BMC, prolotherapy, etc.) in the operative knee within 6 months of ACLR surgery;
7. Steroid injections in the operative knee within 3 months of ACLR surgery;
8. Open growth plates (determined by the treating physician based on standard-of-care preoperative knee radiographs);
9. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) that requires additional anticoagulation beyond usual post-operative standard of care;
10. Current or known history of significant active autoimmune disease (i.e. rheumatoid arthritis and SLE);
11. Incompatible MRI hardware/devices and/or inability to safely undergo MRI per the MRI safety screening questionnaire;
12. Known balance or vestibular disorders, if in the opinion of the Principal Investigator or delegated clinician may affect ability to safely comply with study procedures;
13. History of significant radiation exposure, e.g. due to radiation therapy or occupational exposure;
14. Active malignancy of any type or history of a malignancy within 2 years of informed consent (with the exception of subjects with a history of treated basal or squamous cell carcinoma);

15. Concurrent or previous participation in another clinical trial within 30 days prior to informed consent;

    1. Concurrent enrollment in DOD Project 4, Vail Health Hospital IRB # 2018-20, is allowed while subjects on this study are in the 18-month follow-up period;
    2. Concurrent enrollment in non-interventional registry studies or blood-banking/biomarker studies is allowed;
16. History of substance abuse (drug or alcohol) that may interfere with the subject's ability to cooperate and comply with the trial procedures;

17. Severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the Principal Investigator or delegated clinician, would make the subject inappropriate for entry into this trial.

    Subjects will be withdrawn from the study (Screen Failures) after providing informed consent and/or at the time of ACLR surgery if they meet any of the following criteria:

18. Concurrent reconstruction of any knee ligaments other than the ACL;
19. ACLR which requires the following concomitant treatments: bone plating, metal implants (with the exception of titanium interference screws) or microfracture;
20. Inability to collect sufficient research samples (e.g. less than the minimum required amount of BMA is harvested, or clotting occurs).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Leukocyte-Poor Platelet Rich Plasma (LP-PRP); Participants will have a knee injected with Platelet-Rich Plasma (PRP) obtained from a venous whole blood draw from the vein.	Biological: Leukocyte-Poor Platelet Rich Plasma (LP-PRP); Participants will have a knee injected with Platelet-Rich Plasma (PRP) obtained from a venous whole blood draw from the vein.
Experimental: Bone Marrow Concentrate (BMC); Participants will have a knee injected with BMC stem cells harvested from the iliac crest	Biological: Bone Marrow Concentrate (BMC); Participants will have a knee injected with BMC stem cells harvested from the iliac crest
Placebo Comparator: Control; Patients randomized in the placebo arm will undergo their standard of care treatment and will not receive LP-PRP or BMC.	Other: Control group (Placebo); Participants will undergo ACLR surgery with no injection into their knee.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Occurrence of adverse events	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient reported outcome questionnaire	SF-12 Short Form General Health Survey Patient Satisfaction	screening, baseline, two weeks post-surgery, then every week for 8 weeks post-surgery; 3, 6 12 and 18 months post-surgery
Measure signature cellular profile of BMC	Flow cytometer to analyze BMC cell concentrations	Day of Surgery
Measure plasma levels of pro-inflammatory factors in BMC	Multiplex analysis of pro-inflammatory cytokines and chemokines using Luminex 200®	Day of Surgery
Measure plasma levels of pro-inflammatory factors in LP-PRP	Multiplex analysis of pro-inflammatory cytokines and chemokines using Luminex 200®	Day of Surgery
Quantitative Magnetic Resonance Imaging (MRI)	Images acquired on a 3T Siemens Magnetom Skyra-fit scanner	screening, baseline; 6 and 12 months post-surgery
DSX: three dimensional (3D) to measure motion of the knee using dynamix x-ray software	Up to three brief X-ray exposures (6 scouts x 3 frames and 2 statics x 5 frames and 24 exposures x 100 frames will be acquired)	6 and 12 months post-surgery
Computerized tomography (CT): 3D geometry of bony anatomy using a series of x-rays	single, bilateral knee CT scan using Toshiba Aquilon Premium 160 CT scanner	6 months post-surgery
Patient Reported Outcome questionnaire	IKDC - International Knee Documentation Committee Score	screening, baseline, two weeks post-surgery, then every week for 8 weeks post-surgery; 3, 6 12 and 18 months post-surgery
Patient Reported Outcome questionnaire	WOMAC - Western Ontario & McMaster Universities Osteoarthritis Index	screening, baseline, two weeks post-surgery, then every week for 8 weeks post-surgery; 3, 6 12 and 18 months post-surgery
Patient Reported Outcome questionnaire	Lysholm Score	screening, baseline, two weeks post-surgery, then every week for 8 weeks post-surgery; 3, 6 12 and 18 months post-surgery
Patient Reported Outcome questionnaire	Tegner Activity Scale	screening, baseline, two weeks post-surgery, then every week for 8 weeks post-surgery; 3, 6 12 and 18 months post-surgery
Patient Reported Outcome questionnaire	NRS (NUMERICAL RATING SCALE) for Pain	screening, baseline, two weeks post-surgery, then every week for 8 weeks post-surgery; 3, 6 12 and 18 months post-surgery
Motion Assessment	3D video motion capture	screening, baseline; 6 months post-surgery

Collaborators and Investigators

• Sponsor: Steadman Philippon Research Institute
• Collaborators: United States Department of Defense; Office of Naval Research (ONR)
• Investigators: Principal Investigator: Peter Millett, MD, The Steadman Clinic

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2020
• Primary Completion (Anticipated): March 21, 2024
• Study Completion (Anticipated): September 21, 2024

Study Registration Dates

• First Submitted: December 4, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 19, 2019

Study Record Updates

• Last Update Posted (Actual): April 20, 2023
• Last Update Submitted That Met QC Criteria: April 19, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: stem cell; bone marrow concentrate (BMC); platelet-rich plasma (PRP); anterior cruciate ligament reconstruction (ACLR)
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: 2019-13

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No