Safety, tolerability, clinical, and joint structural outcomes of a single intra-articular injection of allogeneic mesenchymal precursor cells in patients following anterior cruciate ligament reconstruction

A controlled double-blind randomised trial

Yuanyuan Wang, Andrew Shimmin, Peter Ghosh, Paul Marks, James Linklater, David Connell, Stephen Hall, Donna Skerrett, Silviu Itescu, Flavia M. Cicuttini

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13 Citations (Scopus)

Abstract

Background: Few clinical trials have investigated the safety and efficacy of mesenchymal stem cells for the management of post-traumatic osteoarthritis. The objectives of this pilot study were to determine the safety and tolerability and to explore the efficacy of a single intra-articular injection of allogeneic human mesenchymal precursor cells (MPCs) to improve clinical symptoms and retard joint structural deterioration over 24 months in patients following anterior cruciate ligament (ACL) reconstruction. Methods: In this phase Ib/IIa, double-blind, active comparator clinical study, 17 patients aged 18-40 years with unilateral ACL reconstruction were randomized (2:1) to receive either a single intra-articular injection of 75 million allogeneic MPCs suspended in hyaluronan (HA) (MPC + HA group) (n = 11) or HA alone (n = 6). Patients were monitored for adverse events. Immunogenicity was evaluated by anti-HLA panel reactive antibodies (PRA) against class I and II HLAs determined by flow cytometry. Pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36v2 scores. Joint space width was measured from radiographs, and tibial cartilage volume and bone area assessed from magnetic resonance imaging (MRI). Results: Moderate arthralgia and swelling within 24 h following injection that subsided were observed in 4 out of 11 in the MPC + HA group and 0 out of 6 HA controls. No cell-related serious adverse effects were observed. Increases in class I PRA >10% were observed at week 4 in the MPC + HA group that decreased to baseline levels by week 104. Compared with the HA group, MPC + HA-treated patients showed greater improvements in KOOS pain, symptom, activities of daily living, and SF-36 bodily pain scores (p < 0.05). The MPC + HA group had reduced medial and lateral tibiofemoral joint space narrowing (p < 0.05), less tibial bone expansion (0.5% vs 4.0% over 26 weeks, p = 0.02), and a trend towards reduced tibial cartilage volume loss (0.7% vs -4.0% over 26 weeks, p = 0.10) than the HA controls. Conclusions: Intra-articular administration of a single allogeneic MPC injection following ACL reconstruction was safe, well tolerated, and may improve symptoms and structural outcomes. These findings suggest that MPCs warrant further investigations as they may modulate some of the pathological processes responsible for the development of post-traumatic osteoarthritis following ACL reconstruction. Trial registration: ClinicalTrials.gov ( NCT01088191 ) registration date: March 11, 2010.

Original languageEnglish
Article number180
Number of pages12
JournalArthritis Research and Therapy
Volume19
Issue number1
DOIs
Publication statusPublished - 2 Aug 2017

Keywords

  • Anterior cruciate ligament reconstruction
  • Cartilage
  • Function
  • Mesenchymal precursor cells
  • Pain
  • Post-traumatic osteoarthritis
  • Subchondral bone

Cite this

@article{e129b132a74d4364b321ca3be89ad6e0,
title = "Safety, tolerability, clinical, and joint structural outcomes of a single intra-articular injection of allogeneic mesenchymal precursor cells in patients following anterior cruciate ligament reconstruction: A controlled double-blind randomised trial",
abstract = "Background: Few clinical trials have investigated the safety and efficacy of mesenchymal stem cells for the management of post-traumatic osteoarthritis. The objectives of this pilot study were to determine the safety and tolerability and to explore the efficacy of a single intra-articular injection of allogeneic human mesenchymal precursor cells (MPCs) to improve clinical symptoms and retard joint structural deterioration over 24 months in patients following anterior cruciate ligament (ACL) reconstruction. Methods: In this phase Ib/IIa, double-blind, active comparator clinical study, 17 patients aged 18-40 years with unilateral ACL reconstruction were randomized (2:1) to receive either a single intra-articular injection of 75 million allogeneic MPCs suspended in hyaluronan (HA) (MPC + HA group) (n = 11) or HA alone (n = 6). Patients were monitored for adverse events. Immunogenicity was evaluated by anti-HLA panel reactive antibodies (PRA) against class I and II HLAs determined by flow cytometry. Pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36v2 scores. Joint space width was measured from radiographs, and tibial cartilage volume and bone area assessed from magnetic resonance imaging (MRI). Results: Moderate arthralgia and swelling within 24 h following injection that subsided were observed in 4 out of 11 in the MPC + HA group and 0 out of 6 HA controls. No cell-related serious adverse effects were observed. Increases in class I PRA >10{\%} were observed at week 4 in the MPC + HA group that decreased to baseline levels by week 104. Compared with the HA group, MPC + HA-treated patients showed greater improvements in KOOS pain, symptom, activities of daily living, and SF-36 bodily pain scores (p < 0.05). The MPC + HA group had reduced medial and lateral tibiofemoral joint space narrowing (p < 0.05), less tibial bone expansion (0.5{\%} vs 4.0{\%} over 26 weeks, p = 0.02), and a trend towards reduced tibial cartilage volume loss (0.7{\%} vs -4.0{\%} over 26 weeks, p = 0.10) than the HA controls. Conclusions: Intra-articular administration of a single allogeneic MPC injection following ACL reconstruction was safe, well tolerated, and may improve symptoms and structural outcomes. These findings suggest that MPCs warrant further investigations as they may modulate some of the pathological processes responsible for the development of post-traumatic osteoarthritis following ACL reconstruction. Trial registration: ClinicalTrials.gov ( NCT01088191 ) registration date: March 11, 2010.",
keywords = "Anterior cruciate ligament reconstruction, Cartilage, Function, Mesenchymal precursor cells, Pain, Post-traumatic osteoarthritis, Subchondral bone",
author = "Yuanyuan Wang and Andrew Shimmin and Peter Ghosh and Paul Marks and James Linklater and David Connell and Stephen Hall and Donna Skerrett and Silviu Itescu and Cicuttini, {Flavia M.}",
year = "2017",
month = "8",
day = "2",
doi = "10.1186/s13075-017-1391-0",
language = "English",
volume = "19",
journal = "Arthritis Research and Therapy",
issn = "1478-6354",
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number = "1",

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TY - JOUR

T1 - Safety, tolerability, clinical, and joint structural outcomes of a single intra-articular injection of allogeneic mesenchymal precursor cells in patients following anterior cruciate ligament reconstruction

T2 - A controlled double-blind randomised trial

AU - Wang, Yuanyuan

AU - Shimmin, Andrew

AU - Ghosh, Peter

AU - Marks, Paul

AU - Linklater, James

AU - Connell, David

AU - Hall, Stephen

AU - Skerrett, Donna

AU - Itescu, Silviu

AU - Cicuttini, Flavia M.

PY - 2017/8/2

Y1 - 2017/8/2

N2 - Background: Few clinical trials have investigated the safety and efficacy of mesenchymal stem cells for the management of post-traumatic osteoarthritis. The objectives of this pilot study were to determine the safety and tolerability and to explore the efficacy of a single intra-articular injection of allogeneic human mesenchymal precursor cells (MPCs) to improve clinical symptoms and retard joint structural deterioration over 24 months in patients following anterior cruciate ligament (ACL) reconstruction. Methods: In this phase Ib/IIa, double-blind, active comparator clinical study, 17 patients aged 18-40 years with unilateral ACL reconstruction were randomized (2:1) to receive either a single intra-articular injection of 75 million allogeneic MPCs suspended in hyaluronan (HA) (MPC + HA group) (n = 11) or HA alone (n = 6). Patients were monitored for adverse events. Immunogenicity was evaluated by anti-HLA panel reactive antibodies (PRA) against class I and II HLAs determined by flow cytometry. Pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36v2 scores. Joint space width was measured from radiographs, and tibial cartilage volume and bone area assessed from magnetic resonance imaging (MRI). Results: Moderate arthralgia and swelling within 24 h following injection that subsided were observed in 4 out of 11 in the MPC + HA group and 0 out of 6 HA controls. No cell-related serious adverse effects were observed. Increases in class I PRA >10% were observed at week 4 in the MPC + HA group that decreased to baseline levels by week 104. Compared with the HA group, MPC + HA-treated patients showed greater improvements in KOOS pain, symptom, activities of daily living, and SF-36 bodily pain scores (p < 0.05). The MPC + HA group had reduced medial and lateral tibiofemoral joint space narrowing (p < 0.05), less tibial bone expansion (0.5% vs 4.0% over 26 weeks, p = 0.02), and a trend towards reduced tibial cartilage volume loss (0.7% vs -4.0% over 26 weeks, p = 0.10) than the HA controls. Conclusions: Intra-articular administration of a single allogeneic MPC injection following ACL reconstruction was safe, well tolerated, and may improve symptoms and structural outcomes. These findings suggest that MPCs warrant further investigations as they may modulate some of the pathological processes responsible for the development of post-traumatic osteoarthritis following ACL reconstruction. Trial registration: ClinicalTrials.gov ( NCT01088191 ) registration date: March 11, 2010.

AB - Background: Few clinical trials have investigated the safety and efficacy of mesenchymal stem cells for the management of post-traumatic osteoarthritis. The objectives of this pilot study were to determine the safety and tolerability and to explore the efficacy of a single intra-articular injection of allogeneic human mesenchymal precursor cells (MPCs) to improve clinical symptoms and retard joint structural deterioration over 24 months in patients following anterior cruciate ligament (ACL) reconstruction. Methods: In this phase Ib/IIa, double-blind, active comparator clinical study, 17 patients aged 18-40 years with unilateral ACL reconstruction were randomized (2:1) to receive either a single intra-articular injection of 75 million allogeneic MPCs suspended in hyaluronan (HA) (MPC + HA group) (n = 11) or HA alone (n = 6). Patients were monitored for adverse events. Immunogenicity was evaluated by anti-HLA panel reactive antibodies (PRA) against class I and II HLAs determined by flow cytometry. Pain, function, and quality of life were assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36v2 scores. Joint space width was measured from radiographs, and tibial cartilage volume and bone area assessed from magnetic resonance imaging (MRI). Results: Moderate arthralgia and swelling within 24 h following injection that subsided were observed in 4 out of 11 in the MPC + HA group and 0 out of 6 HA controls. No cell-related serious adverse effects were observed. Increases in class I PRA >10% were observed at week 4 in the MPC + HA group that decreased to baseline levels by week 104. Compared with the HA group, MPC + HA-treated patients showed greater improvements in KOOS pain, symptom, activities of daily living, and SF-36 bodily pain scores (p < 0.05). The MPC + HA group had reduced medial and lateral tibiofemoral joint space narrowing (p < 0.05), less tibial bone expansion (0.5% vs 4.0% over 26 weeks, p = 0.02), and a trend towards reduced tibial cartilage volume loss (0.7% vs -4.0% over 26 weeks, p = 0.10) than the HA controls. Conclusions: Intra-articular administration of a single allogeneic MPC injection following ACL reconstruction was safe, well tolerated, and may improve symptoms and structural outcomes. These findings suggest that MPCs warrant further investigations as they may modulate some of the pathological processes responsible for the development of post-traumatic osteoarthritis following ACL reconstruction. Trial registration: ClinicalTrials.gov ( NCT01088191 ) registration date: March 11, 2010.

KW - Anterior cruciate ligament reconstruction

KW - Cartilage

KW - Function

KW - Mesenchymal precursor cells

KW - Pain

KW - Post-traumatic osteoarthritis

KW - Subchondral bone

UR - http://www.scopus.com/inward/record.url?scp=85026656849&partnerID=8YFLogxK

U2 - 10.1186/s13075-017-1391-0

DO - 10.1186/s13075-017-1391-0

M3 - Article

VL - 19

JO - Arthritis Research and Therapy

JF - Arthritis Research and Therapy

SN - 1478-6354

IS - 1

M1 - 180

ER -