Table 1.
Characteristics of the studies included through the systematic review process (studies grouped by drug; those included in the quantitative synthesis are highlighted in bold type)
| Study, year | Location of OA | Treated groups/age of participants (mean ± SD or median [P25–P75]) | Trial duration | Active treatment/formulation regimen | Dose | Data provided in the article (type of AE/% of patients considered) | Published data usable for meta-analysis (yes/no)? | Full data provided by the author/sponsor (source of information)? |
|---|---|---|---|---|---|---|---|---|
| Diclofenac a | ||||||||
| Altman et al. 2009 [29] | Hand | Active: 63.6 ± 10.3 Control: 64.7 ± 9.6 |
8 weeks | Voltaren® gel, consisting of diclofenac sodium in a vehicle | 2 g to each hand four times daily | TEAEs in ≥ 2% of patients: most frequent individual AEs reported; but per SOC frequencies provided for GI and skin AEs; ‘any’, ‘severe’ and ‘withdrawals’ also provided | Yes | Yes (GlaxoSmithKline) |
| Baer et al. 2005 [30] | Knee | Active: 65.0 ± 11.0 Control: 64.6 ± 10.9 |
6 weeks | Diclofenac solution consisting of 1.5% (w/w) diclofenac sodium in a carrier containing DMSO | 10 × 4 drops solution (approximately 1.3 mL), four times daily | Not clear if overall and/or TEAEs reported. Frequencies for individual AEs reported, but not per SOC frequencies | No | No (Nuvo Pharmaceuticals) |
| Baraf et al. 2010 [31] | Knee | Active: 61.8 ± 10.9 Control: 60.9 ± 0.9 |
12 weeks | Diclofenac sodium 1% gel | 4 g per knee four times daily | AEs in ≥ 2% in either group. Detailed report of the most frequent individual AEs, but per SOC frequencies not provided | No | Yes (GlaxoSmithKline) |
| Barthel et al. 2009 [32] | Knee | Active: 59.7 ± 10.5 Control: 59.2 ± 10.6 |
12 weeks | Diclofenac sodium 1% gel | 4 g, four times daily | TEAEs for some SOCs, severe and serious, and detailed specific AEs that occurred in ≥ 3% of patients | Yes | Yes (GlaxoSmithKline) |
| Bookman et al. 2004 [33] (a) vs. vehicle control; (b) vs. placebo control |
Knee | Active: 62.5 ± 11.7 Vehicle: 62.1 ± 11.4 Placebo: 60.8 ± 11.4 |
4 weeks | Diclofenac solution (1.5% w/w diclofenac sodium in a carrier containing DMSO, propylene glycol, glycerin, ethanol and water) | 40 drops of solution (approximately 1.3 mL), four times daily | Not clear if overall and/or TEAEs reported. Frequencies for individual AEs reported, but not per SOC frequencies | No | No (Nuvo Pharmaceuticals) |
| Brühlmann and Michel 2003 [34] | Knee | Active: 64.0 ± 10.7 Control: 64.8 ± 10.6 |
2 weeks | DHEP patch (Flector-EP Tissugel), containing 180 mg of diclofenac epolamine | Patch (10 × 14 cm), applied topically twice daily | Only specific AE frequencies reported, but not per SOC frequencies | No | Yes (author) |
| Dreiser and Tisne-Camus 1993 [36] | Knee | Active: 66.8 ± 1.3 Control: 64.8 ± 1.3 |
2 weeks | DHEP plaster (containing 180 mg of DHEP) | 2 plasters per day | All AEs seem to have been reported | Yes | Yes (Genévrier) |
| Grace et al. 1999 [38] | Knee | Active: 60.4 ± 14.6 Control: 63.6 ± 10.7 |
2 weeks | PHLOJEL® (a pluronic lecithin organogel base) containing 2% diclofenac | 2.5 g, three times daily | Number of AE cases reported, not per SOC frequencies | No | No contact address found |
| Niethard et al. 2005 [40] | Knee | Active: 66 ± 9 Control: 66 ± 9 |
3 weeks | Diclofenac diethylamine gel | 4 g, four times daily | Per SOC AEs reported | Yes | Yes (GlaxoSmithKline) |
| Roth and Shainhouse 2004 [42] | Knee | Active: 63.4 ± 10.5 Control: 64.9 ± 10.6 |
12 weeks | Diclofenac solution consisting of 1.5% (w/w) diclofenac sodium in a patented carrier containing DMSO | Approximately 1.3 mL of solution applied four times daily | Not clear if overall and/or TEAEs reported. Frequencies for individual AEs reported, but not per SOC frequencies | No | No (Nuvo Pharmaceuticals) |
| Wadsworth et al. 2016 [49] | Knee | Active: 60.2 ± 9.2 Control: 61.9 ± 9.1 |
4 weeks | Diclofenac sodium 2% | Approximately 2 mL, i.e. two pumps of the bottle per knee every 12 ± 2 h for 4 weeks | Most common (≥ 3% of patients in either treatment group) TEAEs determined to be related or possibly related to study drug, only for some individual AEs, not per SOC | No | No (author) |
| NCT00171652 | Hand | Active: 64.0 ± 9.7 Control: 63.5 ± 9.8 |
8 weeks | Diclofenac sodium gel 1 % | 2 g, four times daily | Unpublished study | Not applicable | Yes (GlaxoSmithKline) |
| NCT00171626 | Knee | Active: 62.2 ± 9.6 Control: 62.8 ± 10.0 |
12 weeks | Diclofenac sodium gel 1 % | 4 g, four times daily | Unpublished study | Not applicable | Yes (GlaxoSmithKline) |
| Ketoprofen a | ||||||||
|
Conaghan et al. 2013 [35] (a) Ketoprofen 50 mg vs. 2.2 g TDT 064/vehicle (b) Ketoprofen 100 mg vs. 4.4 g TDT 064/vehicle |
Knee | Active (a): 61.6 (37–85) Control (a): 60.1 (24–83) Active (b): 59.9 (26–83) Control (b): 62.3 (37–86) |
12 weeks | Active (a): IDEA-033 (ketoprofen 50 mg) Control (a): Vehicle: TDT 064 (2.2 g ketoprofen-free vehicle) Active (b): IDEA-033 (ketoprofen 100 mg) Control (b): Vehicle: TDT 064 (4.4 g ketoprofen-free vehicle) |
Administered bid (morning and evening) | TRAEs (by SOC and preferred term) in ≥ 1% of patients in any group | Yes | No (Pro Bono Bio) |
|
Kneer et al. 2013 [39] (a) 100 mg ketoprofen (b) 50 mg ketoprofen (c) 25 mg ketoprofen |
Knee | Active (a): 61.8 ± 9.2 Active (b): 61.9 ± 9.7 Active (c): 61.6 ± 9.0 Control: 61.3 ± 9.3 |
12 weeks | Active (a): IDEA-033 100 mg ketoprofen Active (b): IDEA-033 50 mg ketoprofen Active (c): IDEA-033 25 mg ketoprofen |
Either 25, 50, or 100 mg ketoprofen, twice daily | TEAEs in ≥ 1% of patients (by SOC and detailed for Skin and subcutaneous tissue disorders), and TRAEs (overall) for some of the SOCs | Yes | No (Pro Bono Bio) |
| Rother et al. 2007 [44] | Knee | Active: 63.3 ± 10.1 Control: 62.8 ± 9.8 |
6 weeks | Ketoprofen in 4.8 g transfersome (a semi-solid formulation, IDEA-033) | 110 mg epicutaneous ketoprofen in 4.8 g transfersome every 12 h | Most commonly reported AEs (by SOC and specific AEs); percentage of patients considered not specified | Yes | No (Pro Bono Bio) |
| Rother and Conaghan 2013 [43] | Knee | Active: 61.8 ± 11.3 Control: 62.6 ± 9.5 |
12 weeks | 100 mg ketoprofen in 4.4 g transfersome gel (IDEA-033) |
Twice daily at 12-h intervals | TRAEs in > 1% of patients in either group | Yes | No (Pro Bono Bio) |
| Ibuprofen a | ||||||||
| Rovensky et al. 2001 [45] | Knee | Active: 62.73 ± 7.33 Control: 64.15 ± 9.06 |
1 week | 5% ibuprofen cream | One 10-cm strip of cream (200 mg of Ibuprofen for the active sample), three times daily | All AEs seem to have been reported | Yes | No (author) |
| Trnavský et al. 2004 [47] | Knee | Active: 67.0 ± 6.7 Control: 66.9 ± 7.5 |
1 week | 5% ibuprofen cream (Dolgit®) | One 10-cm strip of cream three times daily (equivalent to 3 × 4 g of cream and 3 × 200 mg ibuprofen) | All AEs seem to have been reported | Yes | No (author) |
| Varadi et al. 2013 [48] | Knee | Active: 60.8 ± 11.6 Control: 61.8 ± 11.0 |
2 weeks | Ibuprofen formulated in a cream containing 10% (w/w) ibuprofen | 2 g of cream twice daily | All AEs seem to have been reported | Yes | Yes (author) |
| Eltenac | ||||||||
| Ottillinger et al. 2001 [41] (a) Eltenac gel 1% (b) Eltenac gel 0.3 % (c) Eltenac gel 0.1% |
Knee | Active (a): 66 ± 8 Active (b): 66 ± 9 Active (c): 67 ± 8 Control: 67 ± 7 |
4 weeks | Active (a): Eltenac gel 1% Active (b): Eltenac gel 0.3% Active (c): Eltenac gel 0.1% |
3 g of the gel (a string approximately 10 cm long), three times daily, corresponding to daily eltenac doses of 90 mg (1% gel), 27 mg (0.3% gel) and 9 mg (0.1% gel) | Summary/not detailed | No | No (author) |
| Sandelin et al. 1997 [46] | Knee | Active: 61 ± 8.3 Control: 61 ± 7.8 |
4 weeks | Eltenac 1% gel | 3 g (= 30 mg eltenac), three times daily | Possibly TRAEs (by SOC and summary for specific AEs) | Yes | Author contacted with no response |
| Piroxicam | ||||||||
|
Allegrini et al. 2009 [28] (a) Patch with 14 mg of piroxicam (b) Piroxicam 1% cream (no specific placebo) |
Lumbar | Active Patch: 51 ± 13 Control Patch: 52 ± 13 |
1 week | Patch containing 14 mg of piroxicam | One patch containing 14 mg of piroxicam applied once daily | Numbers of AEs reported, not frequencies | No | Yes (author) |
| Nimesulide | ||||||||
| Ergün et al. 2007 [37] | Knee | Active: 54.2 ± 9.0 Control: 53.1 ± 10.1 |
4 weeks | Nimesulide gel (Sulidin gel 1%) | Approximately 0.4 mg/10 cm2, three times daily | All AEs seem to have been reported | Yes | Yes (author) |
| S-flurbiprofen | ||||||||
|
Yataba et al. 2017 [50] (a) 10 mg of S-flurbiprofen (b) 20 mg of S-flurbiprofen (c) 40 mg of S-flurbiprofen |
Knee | Active (a): 66.7 ± 9.6 Active (b): 66.4 ± 9.3 Active (c): 66.2 ± 8.6 Control: 67.3 ± 9.1 |
2 weeks | Active (a): 10 mg of S-flurbiprofen Active (b): 20 mg of S-flurbiprofen Active (c): 40 mg of S-flurbiprofen |
One patch (10 × 14 cm) of the assigned study drug to cover the tender point of the evaluated knee, replaced once daily | Focus on overall application site and systemic AEs and their relation to the treatment. Per SOC report of all TEAEs not provided | No | Yes (author) |
Where published data were adequate for inclusion in the meta-analysis and full safety report, also provided by the author/sponsor, we preferably used the full data obtained from the author/sponsor
AE adverse event, bid twice daily, DHEP diclofenac hydroxyethylpyrrolidine, DMSO dimethyl sulfoxide, GI gastrointestinal, OA osteoarthritis, SD standard deviation, SOC System Organ Class, TEAEs treatment-emergent adverse events, TRAEs treatment-related adverse events
aDrug with sufficient data for ‘individual meta-analysis’