Safety and efficacy of an allogeneic adipose-derived mesenchymal stem cell preparation in the treatment of knee osteoarthritis: A Phase I/IIa randomised controlled trial

Abstract

Objectives: To assess the safety and efficacy of an allogeneic adipose-derived mesenchymal stem cell preparation (MAG200) in the treatment of knee osteoarthritis over 12 months.

Design: A single-centre, double-blind, ascending dose, randomised controlled trial. 40 participants with moderate knee osteoarthritis were randomised to receive a single intra-articular injection of MAG200 (dose cohorts:10, 20, 50, 100 ​× ​10⁶ ​cells) or placebo. Primary objectives were safety and efficacy according to a compound responder analysis of minimal clinically important difference in pain (numerical pain rating scale [NPRS]) and function (Knee Injury and Osteoarthritis Outcome Score - Function in Daily Living subscale [KOOS_ADL]) at month 12. Secondary efficacy outcomes included changes from baseline in patient reported outcome measures and evaluation of disease-modification using quantitative MRI.

Results: Treatment was well tolerated with no treatment-related serious adverse events. MAG200 cohorts reported a greater proportion of responders than placebo and demonstrated clinical and statistically significant improvement in pain and clinically relevant improvement in all KOOS subscales. MAG200 demonstrated a reproducible treatment effect over placebo, which was clinically relevant for pain in the 10 ​× ​10⁶ dose cohort (mean difference NPRS:-2.25[95%CI:-4.47,-0.03, p ​= ​0.0468]) and for function in the 20 ​× ​10⁶ and 100 ​× ​10⁶ dose cohorts (mean difference KOOS_ADL:10.12[95%CI:-1.51,21.76, p ​= ​0.0863] and 10.81[95%CI:-1.42,23.04, p ​= ​0.0810] respectively). A trend in disease-modification was observed with improvement in total knee cartilage volume in MAG200 10, 20, and 100 ​× ​10⁶ dose cohorts, with progression of osteoarthritis in placebo, though this was not statistically significant. No clear dose response was observed.

Conclusion: This early-phase study provides supportive safety and efficacy evidence to progress MAG200 to later-stage trial development.

Trial registration: ACTRN12617001095358/ACTRN12621000622808.

Keywords: Allogeneic; Cartilage; Disease modification; Intra-articular; Knee; Mesenchymal stem cells; Osteoarthritis; Regenerative medicine.

Fig. 1

Participant flow chart (CONSORT).

Fig. 2

Key Secondary Endpoints – Change from baseline in pain (NPRS) and in KOOS Function in Daily Living (KOOS_ADL). Error bars represent ±1 times the standard error of the mean value. The horizontal black line represents the Minimum Clinically Important Difference (MCID) from baseline score. Values below this line for NPRS are considered clinically meaningful. Values above this line for KOOS are considered clinically meaningful. NS ​= ​change from baseline is not statistically significant (p ​> ​0.05). ∗ ​= ​change from baseline is statistically significant (p ​≤ ​0.05 but p ​> ​0.01). ∗∗ ​= ​change from baseline is statistically significant (p ​≤ ​0.01 but p ​> ​0.001). ∗∗∗ ​= ​change from baseline is statistically significant (p ​≤ ​0.001).

Fig. 3

Change from baseline in all other KOOS subscales. Error bars represent ±1 times the standard error of the mean value. The horizontal black line represents the Minimum Clinically Important Difference (MCID) from baseline score. Values above this line are considered clinically meaningful. NS ​= ​change from baseline is not statistically significant (p ​> ​0.05). ∗ ​= ​change from baseline is statistically significant (p ​≤ ​0.05 but p ​> ​0.01). ∗∗ ​= ​change from baseline is statistically significant (p ​≤ ​0.01 but p ​> ​0.001). ∗∗∗ ​= ​change from baseline is statistically significant (p ​≤ ​0.001).

Fig. 4

Estimates of treatment effect (MAG200 minus placebo) on pain reduction (NPRS) at month 12. Mean Difference ​= ​estimate of treatment effect and represents change from baseline on active treatment minus change from baseline on placebo. Pain as measured by NPRS. Values further to the left support a greater reduction in pain from baseline in MAG200 cohorts compared to placebo. Vertical dotted line represents the Minimum Clinically Important Difference (MCID) from placebo. MD ​= ​Mean Difference, LCL/UCL ​= ​Lower/Upper 95% Confidence Limit.

Fig. 5

Estimates of treatment effect (MAG200 minus placebo) on pain and function as measured by KOOS subscales at month 12. Mean Difference ​= ​estimate of treatment effect and represents change from baseline on active treatment minus change from baseline on placebo. Values further to the right support a greater improvement in KOOS subscale scores in MAG200 cohorts in comparison to placebo. Vertical dotted line represents the Minimum Clinically Important Difference (MCID) from placebo. MD ​= ​Mean Difference, LCL/UCL ​= ​Lower/Upper 95% Confidence Limit.

Fig. 6

Quantitative MRI analysis. (A) Single sagittal T1-weighted fat saturated image of a participant's knee with outline used to calculate segmental cartilage volume. (B) Single sagittal T2 mapping image of a participant's knee showing calculated segmental cartilage T2-value assessment.