Table 3.
Published results of phase II/III clinical trials related to the repurposed 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 | |||||||||
| Clodronate | |||||||||
| Frediani et al. 32 | – | Knee | Clodronate IM 200 mg/day for 15 days and then once weekly for next 2.5 months Clodronate IM 200 mg/day for 15 days and then once weekly for next 11.5 months |
37 37 |
12 months | 50.3 ± 31.9 (SD) 15.6 ± 9.8 (SD)* (VAS = 0–100) |
24.0 ± 11.9 13.5 ± 5.7* |
NA | NA |
| Zoledronic acid | |||||||||
| Cai et al. 33 | ACTRN12613000039785 Phase III |
Knee | Placebo saline IV Zoledronic acid IV 5 mg baseline and 12 months |
110 113 |
24 months | −16.8 (−22.0 to −11.6) −11.5 (−16.9 to −6.2) (VAS) |
NA | NA | NA |
| Vitamin D | |||||||||
| Perry et al. 34 | – | Knee | Placebo Cholecalciferol oral 800 IU/day |
26 24 |
24 months | NA | NA | Change from baseline 61.5 (−1085.6 to 1208.6) 155.4 (−1097.3 to 1408.0) (synovial volume mm3) − 193.4 (−2845.7 to 2459.0) −506.9 (−3395.6 to 2381.9) (subchondral BML volume mm3) |
|
| MacFarlane et al. 35 | NCT01351805 | Knee | Placebo Cholecalciferol oral 2000 IU/day |
630 591 |
4 years | 34.6 ± 0.9 (SE) 32.7 ± 0.9 |
34.6 (0.9) (SE) 34.1 (1.0) |
||
| Synovitis-driven endotype | |||||||||
| Methotrexate | |||||||||
| Kingsbury et al. 36 | ISRCTN77854383 Phase III |
Knee | Placebo 10–25 mg over 8 weeks and then maintenance at 25 mg |
68 66 |
6 months | −0.83 (−1.55, −0.10) (mean difference, NRS pain) | –5.01 (−8.74, −1.29) | NA | 14.89 (–18.19, 47.96) (mean difference, mm3) |
| Ferrero et al. 37 |
NCT01068405 Phase III |
Hand | Placebo 10 mg MTX for 12 months |
32 32 |
12 months | 17.8 (29) 14.3 (19) Mean change from baseline (SD), VAS pain range (0–100) |
0.2 (5) 0.33 (5) Change from baseline (SD) FIHOA score range (0–30) |
No significant change in Verbruggen-Veys score and GUSS | No significant difference in MRI synovitis and other lesions |
| Hydroxychloroquine | |||||||||
| Lee et al. 38 |
NCT 01148043 Phase III |
Hand | Placebo HCQ 400 mg once a day for 24 weeks |
98 98 |
24 weeks | +1.1 mm (95% CI: −4.2 to 6.4) 1.1 mm (95% CI: −6.7 to 4.1) Mean change from baseline, VAS pain range 0–100 |
No significant change for AUSCAN and AIMS2-SF | NA | NA |
| Kingsbury et al. 39 | ISRCTN91859104 | Hand | Placebo HCQ (200–400 mg) for 12 months (maximum 6.5 mg/kg per day) |
119 113 |
12 months | 5.51 (95% CI: 4.98 to 6.04) 5.39 (95% CI: 4.83 to 5.92) Mean score, NRS pain 0–10 |
18.74 (17.30 to 20.18) 19.72 (18.24 to 21.20) AUSCAN |
48.30 (47.50 to 49.10) 48.14 (47.32 to 48.96) Kallman total radiographic score range (0–220) |
NA |
| Kedor et al. 40 | ISRCTN46445413 | Hand | Placebo 200 mg/day, 200 and 400 mg every other day or 200 mg two times a day according to body weight |
78 75 |
52 weeks | 26.5 (23.9 to 29.1) 26.7 (23.9 to 29.4) Mean score at 52 weeks |
51.3 (46.6 to 56.0) 48.1 (43.0 to 53.2) |
46.8 (95% CI: 45.7 to 47.8) 47.1 (95% CI: 4.60 to 4.82) |
|
| Etanercept | |||||||||
| Kloppenburg et al. 41 | Hand | Placebo Etanercept SC 50 mg weekly for the first 24 weeks, followed by 25 mg weekly thereafter |
45 45 |
1 year | 45.4 (25.7) 35.7 (25.1) Mean score (SD) VAS pain range 0–100 |
10.9 (9.9) 9.9 (5.9) FIHOA |
288 (34) (n = 31) 287 (36) (n = 23) GUSS |
Synovitis (n = 10 each) 1.4 (0.3) 1.0 (0.5) BMLs (n = 10 each) 0.7 (0.3) 0.6 (0.3) |
|
| Tocilizumab | |||||||||
| Richette et al. 42 |
NCT02477059 Phase III |
Hand | Placebo Tocilizumab 8 mg/kg IV at weeks 0 and 4 |
41 42 |
6 weeks | −9.9 (SD: 20.1) −7.9 (SD: 19.4) VAS pain range 0–100 |
0.2 ± 0.6 −0.04 ± 0.6 FIHOA (0–30) |
||
| Other mechanisms | |||||||||
| Liraglutide | |||||||||
| Gudbergsen et al. 43 |
NCT02905864 Phase IV |
Knee | Placebo liraglutide 3 mg/day for 52 weeks |
76 80 |
52 weeks | −0.6 (−4.4, 3.3) 0.4 (−3.3, 4.0) Mean change from baseline, KOOS symptom |
−1.6 (−5.1, 1.9) 1.4 (−2.0, 4.8) Mean change from baseline, KOOS function |
NA | NA |
*
denotes P ≤ 0.05, active vs control. AIMS2-SF, Arthritis Impact Measurement Scale 2–Short Form; AUSCAN, Australian Canadian Hand Osteoarthritis Index; BML, bone marrow lesion; CI, confidence interval; DMOAD, disease-modifying osteoarthritis drug; FIHOA, Functional Index for Hand Osteoarthritis; GUSS, Ghent University Scoring System; HCQ, hydroxychloroquine; IM, intramuscular; IV, intravenous; KOOS, Knee injury and Osteoarthritis Outcome Score; MRI, magnetic resonance imaging; MTX, methotrexate; NA, non-available; NRS, Numerical Rating Scale; OA, osteoarthritis; SC, subcutaneous; SD, standard deviation; VAS, Visual Analogue Scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.