Table 1.
Characteristics of the studies included from the systematic review process, according to the pre-specified selection criteria (without concomitant OA treatment; those studies ultimately included in the meta-analysis are highlighted in bold type)
| Study | Location of OA | Treated groups/age of participants (mean ± SD or median [P25–P75]) | Origin of HA | Molecular weight | Dose | Number of cycles/number of injections per cycle | Follow-up duration (weeks) | Data provided in the article (type of AE/% of patients considered) | Published data usable for M-A? (yes/no) | Full data provided by the author/sponsor? (source of information) |
|---|---|---|---|---|---|---|---|---|---|---|
| Altman 1998 [51] | Knee | IA HA: 62 ± 10 IA SA: 65 ± 10 |
Avian sodium hyaluronate | 500–730 kDa | 2 mL (20 mg) HA in saline vehicle | 1/5 | 26 weeks | Most commonly occurring AEs (> 5%) on all randomized patients | Yes | No (Fidia Pharma) |
| Altman 2004 [52] | Knee | IA HA: Mean: 62.9 Range : 41–85 IA SA: Mean: 63.3 Range: 35–85 |
Streptococci [Non-animal stabilized hyaluronic acid (NASHA)] | NA | 3 mL injection : 60 mg HA in buffered sodium chloride, 0.9% | 1/1 | 26 weeks | Summary according to the relationship of AEs to the treatment. Data for TRAEs (the most common) and serious AEs | Yes | No (Author) |
| Arden 2014 [53] | Knee | IA HA: 64.5 (29–84) IA SA: 60.9 (30–86) |
NA | NA | 60 mg, single IA injection | 1/1 | 6 weeks | TRAEs/Summary | No | No (Author) |
| Baltzer 2009 [54] | Knee | IA HA: 57.4 ± 12.0 IA SA: 60.3 ± 10.7 |
NA | 1.4 x 106 Da | 2 mL of HA (1% solution of HA) | 1/3 | 29 weeks | Results mainly presented as percentages and numbers of patients with ‘mild’, ‘moderate’, ‘severe’ AEs. Frequencies reported for some SOCs | Yes | Author contacted with no response |
| Brandt 2001 [55] | Knee | IA HA: 65 ± 8.4 IA SA: 67 ± 8.4 |
Avian (Rooster combs) | 1.0–2.9 million Da | 2 mL (15 mg/mL) | 1/3 | 27 weeks | AEs reported by ≥ 5 % of the patients (by Body System) | Yes | Author contacted with no response |
| Carrabba 1995 [56] | Knee | IA HA 1 injection: 61.3 ± 6.8 IA HA 3 injections: 60.0 ± 7.1 IA HA 5 injections: 60.6 ± 7.9 IA Placebo: 60.0 ± 7.0 |
Avian (Rooster combs) | 500–730 kDa | 20 mg/2 mL, 1, 3 or 5 injections | 1/1, 3 or 5 | 26 weeks | Summary; focus on local AEs. | No | No contact information found |
| Cohen 2008 [57] | Ankle | IA HA: 56.2 ± 15.1 IA SA: 43.4 ± 14.9 |
NA | 500–730 kDa | NA (2 mL HYL) | 1/5 | 26 weeks | Summary/Not detailed | No | Author contacted with no response |
| DeCaria 2012 [58] | Knee | IA HA: 71.93 ± 6.83 IA inert HA (Placebo): 72.93 ± 5.48 |
NA | 730 kDa | 2ml of 20 mg/ml HA | 1/3 | 26 weeks | Summary/Not detailed. | No | Author contacted with no response |
| DeGroot 2012 [59] | Ankle | IA HA: 54.1 ± 14.5 IA SA: 61.9 ± 14.1 |
Avian derivate (derived from rooster combs) | 620,000 to 1,170,000 Da | Each 2.5 mL of Supartz contains 25 mg of sodium hyaluronate | 1/1 | 12 weeks | Summary/Not detailed | No | Author contacted with no response |
| Diracoglu 2009 [60] | Knee | IA HA: 59.4 ± 9.9 IA SA: 56.2 ± 7.2 |
NA | NA | NA | 1/3 | NA (Short-term study. ‘Injections were repeated in both groups three times after every one-week’) | Summary/Not detailed | No | Author contacted with no response |
| Dixon 1988 [61] | Knee | IA HA and IA SA: Mean: 68.5 Range: 43–85 | NA | NA | 20 mg sodium hyaluronate (2 mL) | 1/11 | 48 weeks | Treatment related or possibly related AEs reported. | Yes | No (Fidia Pharma) |
| Gormeli 2017 [62] | Knee | IA HA: 53.5 ± 14 IA SA: 52.8 ± 12.8 |
NA | NA (‘A high molecular weight HA’) | 2 mL (30 mg/ 2 mL HA) | 1/3 | 26 weeks | AEs assessed, but results not reported | No | Author contacted with no response |
| Hangody 2017 [63] | Knee | IA HA: 59.2 ± 8.6 IA SA: 58.0 ± 9.0 |
NA | NA | 4 mL, 88 mg HA | 1/1 | 26 weeks | Summary: numbers of AEs reported, not frequencies | No | Yes, data sent by the author as “Number of AEs - By Severity” and not frequencies; not adequate for M-A |
| Huang 2011 [64] | Knee | IA HA: 65.9 ± 8.1 IA SA: 64.2 ± 8.4 |
Avian (naturally derived from rooster combs) | 500–730 kDa | 20 mg HA /2 mL | 1/5 | 25 weeks | Summary/Not detailed. Number of SAEs reported, not frequencies | No | No (Fidia Pharma) |
| Jorgensen 2010 [65] | Knee | IA HA: 62.6 ± 11.4 IA SA: 61.4 ± 11.1 |
NA | NA | 2 ml Hyalgan (10 mg/ml) | 1/5 | 13 weeks to a maximum of 52 weeks after the 1st injection | Summary/Not detailed. Per group numbers of AEs reported | No | Yes (Author) |
| Karlsson 2002 [66] | Knee | IA HA (Artzal): 72 ± 7 IA HA (Synvisc): 70 ± 7 IA SA: 71 ± 6 |
NA | Artzal : ~106 Da Synvisc : ~7 x 106 Da |
Artzal: 2.5 ml (1% HA); Synvisc : 2.0 ml (0.8% HA) |
1/3 | 52 weeks | Summary/Not detailed. Number of AEs reported, not the frequencies of specific AEs | No | No (Author) |
| Kotevoglu 2006 [67] | Knee | IA HA (Orthovisc) : 58.6 ± 8.0 IA HA (Synvisc) : 59.7 ± 8.0 IA SA : 60.1±5.4 |
NA | NA (Orthovisc: Low molecular weight Synvisc: High molecular weight) |
NA | 1/3 | 26 weeks | Summary/Not detailed | No | Author contacted with no response |
| Kul-Panza 2010 [68] | Knee | IA HA: 59.5 ± 8.8 IA SA: 62.8 ± 7.8 |
NA | 1.5 million Da (average) | 2 mL 1.5% (15 mg/mL) of intra-articular HA | 1/9 (3 injections a week, for 3 consecutive weeks). | 14 weeks | Summary/Not detailed | No | Clarifications from the author not sufficient for inclusion of this study in the M-A |
| Petrella 2002 [69] | Knee | IA HA (+ Placebo tablet): 67.3 ± 8.9 IA SA (+ Placebo tablet): 62.6 ± 9.5 |
NA (Suplasyn) | NA | 2ml, 10mg/ml | 1/3 | 12 weeks | Summary/Not detailed | No | Author contacted with no response |
| Puhl 1993 [70] | Knee | IA HA: 62.1 (41–75) IA SA: 60.8 (40–74) |
Avian (Rooster combs) | 6.0–12.0 × 105 Da | 25 mg of sodium hyaluronate/ 2.5 ml | 1/5 | 18 weeks | All AEs seem to have been reported (treatment-related and others) | Yes | No contact information found |
| Salk 2006 [71] | Ankle | IA HA: 57.8 ± 14.7 IA SA: 60.0 ± 13.9 |
NA | 500–730 kDa | 1 mL of hyaluronic acid (10 mg/mL) | 1/5 | 26 weeks | Detailed report of AEs: usable for analysis | Yes | Author contacted with no response |
| Van der Weegen 2015 [72] | Knee | IA HA: 58.7 ± 9.6 IA SA: 60.1 ± 10.1 |
Produced from the bacterium Streptococcus equi by a process of continuous fermentation. | 2.2 M Da | 1.5 % HA (30 mg/2 ml) | 1/3 | 29 weeks | Summary/Not detailed | No | Yes (Author) |
Where published data were adequate for inclusion in the M-A and a full safety report was also provided by the author/sponsor, we preferentially used the full data obtained from the author/sponsor
AE adverse event, HA hyaluronic acid, IA intra-articular, IAHA intra-articular hyaluronic acid, IASA intra-articular saline, M-A meta-analysis, NA not available (i.e. information not provided in the manuscript), OA osteoarthritis, SAE serious adverse event, SOC System Organ Class, TRAEs treatment-related adverse events