Table 4.
Published results of phase II/III clinical trials related to the investigational DMOAD agents since 2017 by OA endotypes.
| Authors/References | ClinicalTrials.gov Identifier/trial phase |
OA site | Dosage, route of interventions | n | Longest follow-up | Efficacy in symptomatic modification | Efficacy in structural modification | ||
|---|---|---|---|---|---|---|---|---|---|
| Pain (0–50) (WOMAC if not denoted otherwise) | Function (0–170) (WOMAC if not denoted otherwise) | Plain X-rays | MRI | ||||||
| Bone-driven endotype | |||||||||
| Cathepsin K inhibitors | |||||||||
| Conaghan et al. 113 |
NCT02705625 NCT03037489 Phase II |
Knee | Placebo MIV-711, 100 mg/day MIV-711, 200 mg/day |
80 82 82 |
26 weeks | −1.4 (−1.9 to −0.8) −1.7 (−2.3 to −1.2) −1.5 (−2.0 to −0.9) NRS (0–10) |
NA | NA | 23.3 (15.7 to 30.9) 7.9 (0.5 to 15.3)** 8.6 (1.1 to 16.1)** (Bone area, mm2) −0.066 (−0.119 to −0.013) 0.011 (−0.042 to 0.063)* −0.022 (−0.074 to 0.031) (Cartilage thickness, mm) |
| Matrix extracellular phosphoglycoprotein | |||||||||
| McGuire et al. 114 | – Phase II |
Knee | Placebo TPX-100 IA 200 mg 4 weekly injections |
93 93 |
12 months | – Significant WOMAC scores (No numerical data) |
– Significant WOMAC scores (No numerical data) |
NA | No significance in cartilage thickness/volume on quantitative MRI (No numerical data) |
| McGuire et al. 115 | – Phase II |
Knee | Placebo TPX-100 IA 200 mg 4 weekly injections |
78 78 |
12 months | NA | Significant decrease in pathologic bone shape change in the femur (No numerical data) |
||
| Synovitis-driven endotype | |||||||||
| Diacerein | |||||||||
| Pelletier et al. 116 |
NCT02688400 Phase II |
Knee | Diacerein 50 mg OD for 1 month and then BD celecoxib 200 mg OD |
140 148 |
6 months | −11.1 (0.9) −11.8 (0.9) |
−27.2 (39.0) −29.3 (39.8) |
||
| Cartilage-driven endotype | |||||||||
| Proteinase inhibitors | |||||||||
| Galapagos and Servier 117 |
NCT03595618 Phase II |
Knee | Placebo S201086/GLPG1972 low dose S201086/GLPG1972 medium dose S201086/GLPG1972 high dose (no numerical report) |
932 (total) | 52 weeks | No significance (no numerical report) |
No significance (No numerical report) |
NA | −0.116 (0.27) −0.068 (0.20) −0.097 (0.27) 0.085 (0.22) Change in cartilage thickness (in mm (SD)) |
| Fibroblast growth factor 18 | |||||||||
| Lohmander et al. 118 |
NCT01033994 Phase Ib |
Knee | Placebo Sprifermin IA 10 µg 3 once weekly Sprifermin IA 30 µg 3 once weekly Sprifermin IA 100 µg 3 once weekly |
42 21 42 63 |
12 months | −5.56 (4.17) −4.10 (5.11) −3.54 (3.67) −2.87 (4.76)* (Mean change from baseline, SD) |
−17.02 (13.56) −15.76 (13.72) −12.12 (12.06) −11.28 (15.30)* (Mean change from baseline, SD) |
−0.02 (0.90) 0.05 (1.00) 0.03 (0.72) −0.04 (0.90) (Mean change, MFTC JSW, mm) −0.18 (0.74) −0.02 (0.86) 0.0 (0.73) 0.34 (0.90)* (Mean change, LFTC JSW, mm) |
−0.11 (−0.20, −0.02) 0.02 (−0.18, 0.23) −0.11 (−0.18, −0.03) −0.03 (−0.11, 0.04) (Mean change, cMFTC cartilage thickness, mm) −0.03 (−0.04, 0.01) 0.00 (−0.08, 0.08) −0.01 (−0.02, 0.01) 0.01 (0.00, 0.03)* (Mean change, TFTC cartilage thickness, mm) |
| Hochberg et al. 119 |
NCT01919164 Phase II |
Knee | Placebo Sprifermin IA 30 µg 3 once weekly q6mo Sprifermin IA 30 µg 3 once weekly q12mo Sprifermin IA 100 µg 3 once weekly q6mo Sprifermin IA 100 µg 3 once weekly q12mo |
108 111 110 110 110 |
24 months | NA 2.58 (–3.47, 8.64) 1.29 (–4.53, 7.10) −0.06 (–5.76, 5.65) 3.65 (–1.99, 9.28) (Difference with placebo; total WOMAC score) |
No numerical data for individual WOMAC scores | NA 0.08 mm (−0.08, 0.25) 0.04 mm (−0.13, 0.20) 0.26 mm (0.12, 0.40)** 0.26 mm (0.12, 0.41)** (Difference versus placebo, LFTC JSW, mm) |
−0.02 (−0.04, −0.01) 0.00 (−0.02, 0.02) −0.01 (−0.03, 0.00) 0.03 (0.01, 0.04) 0.02 (0.00, 0.03)*** (Mean change, LFTC cartilage thickness, mm) |
| Eckstein et al. 120 |
NCT01919164 Phase II |
Knee | Placebo Sprifermin IA 30 µg 3 once weekly q12mo Sprifermin IA 30 µg 3 once weekly q6mo Sprifermin IA 100 µg 3 once weekly q12mo Sprifermin IA 100 µg 3 once weekly q6mo |
108 110 111 110 110 |
60 months | −22.38 (22.19) −24.41 (22.48) −20.38 (22.49) −24.94 (19.95) −24.00 (22.38) (Change from baseline at 5 years) |
−17.03 (24.15) −18.74 (21.87) −18.55 (23.76) −18.82 (21.62) −18.56 (23.60) |
−0.38 (0.72); mean (SD) −0.47 (1.02) −0.31 (0.75) −0.27 (0.75) −0.16 (0.77) Change from baseline at 5 years; MFTC JSW, mm −0.13 (0.65) −0.05 (0.60) −0.03 (0.69) 0.03 (0.88) 0.02 (0.76) Change from baseline at 5 years; LFTC JSW, mm |
– – – –* No numerical data reported for LFTC cartilage thickness |
| Transforming growth factor-β | |||||||||
| Guermazi et al. 121 |
NCT01221441 Phase II |
Knee | placebo IA (2 ml normal saline 0.9%) TissueGene-C IA | 29 57 |
12 months | NA | NA | – | 47.9% 34.6% Progression of cartilage morphology in any subregion 21.1% 9.6% Any worsening in Hoffa-synovitis/effusion-synovitis combined 60.6% 66.2% Any BML progression 32.4% 31.6% Any meniscal damage progression |
| Lee et al. 122 |
NCT01221441 Phase II |
Knee | Placebo IA (2 ml normal saline 0.9%) TissueGene-C IA | 35 67 |
12 months | Significant, improvement in VAS pain | Significant, improvement in IKDC scores | – | 47.9% 34.6% Progression of cartilage morphology in any subregion 21.1% 9.6% Any worsening in Hoffa-synovitis/effusion-synovitis combined |
| Kim et al. 123 | – Phase III |
Knee | Placebo IA (2 ml normal saline 0.9%) TissueGene-C IA | 81 78 |
12 months | –10 –25*** (Change from baseline, VAS pain score) |
NA | Not significant (JSW) | No significant change in any of WORMS subscore |
| Wnt/β-catenin signalling pathway inhibitors | |||||||||
| Yazici et al. 124 |
NCT02536833 Phase IIa |
knee | Placebo Lorecivivint (SM04690) 0.03 mg Lorecivivint (SM04690) 0.07 mg Lorecivivint (SM04690) 0.23 mg |
114 112 117 109 |
13 weeks | −22.1 ± 2.1 −23.3 ± 2.2 −23.5 ± 2.1 −23.5 ± 2.1 (Mean ± SD change from baseline) |
NA | −0.20 mm −0.07 mm −0.11 mm −0.02 mm* (Mean ± SD change from baseline, medial JSW) |
NA |
| Yazici et al. 125 |
NCT03122860 Phase IIb |
Knee | Dry needle Placebo Lorecivivint (SM04690) 0.03 mg Lorecivivint (SM04690) 0.07 mg Lorecivivint (SM04690) 0.15 mg Lorecivivint (SM04690) 0.23 mg |
117 116 116 115 115 116 |
24 weeks | NA 6.2 (1.0) 6.2 (1.1)* 6.1 (1.1) 6.1 (1.0) 6.1 (1.0)* (Mean ± SD change from baseline, NRS pain) |
NA 59.2 (9.8) 59.0 (10.9) 58.1 (11.2) 57.7 (11.1) 57.3 (11.4)* (Mean ± SD change from baseline) |
NA 3.44 (1.31) 3.30 (1.26) 3.16 (1.10) 3.26 (1.24) 3.27 (1.08) (Mean ± SD change from baseline, medial JSW) |
NA |
| Senolytic agents | |||||||||
| UNITY Biotechnology 126 |
NCT04129944 Phase II |
Knee | Placebo UBX0101 IA 0.5 mg UBX0101 IA 2.0 mg UBX0101 IA 4.0 mg |
46 45 46 46 |
12 weeks | −1.017 −0.924 −1.052 −1.019 (Mean change from baseline) |
NA | NA | NA |
*
, **, and *** denote P ≤ 0.05, P ≤ 0.01, and P ≤ 0.001, respectively, active vs control. BD, bis die; BML, bone marrow lesion; cMFTC, central medial femorotibial compartment; DMOAD, disease-modifying osteoarthritis drug; IA, intra-articular; IKDC, international knee documentation committee; JSW, joint space width; LFTC, lateral femorotibial compartment; MFTC, medial femorotibial compartment; MRI, magnetic resonance imaging; NA, non-available; NRS, Numerical Rating Scale; OA, osteoarthritis; OD, omne in die; SD, standard deviation; VAS, Visual Analogue Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index. WORMS, whole organ magnetic resonance imaging score.