Table 2.
Characteristics of studies included in the parallel qualitative synthesis (trials with concomitant OA treatment allowed; those studies ultimately included in the parallel 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) | Concomitant OA treatment (medication) allowed | 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 2009 [73] | Knee | IA HA: 62,5 ± 11 IA SA: 60,8 ± 10 |
Derived from nonpyogenic Streptococcus zooepidemicus (biologic fermentation) | 2.4–3.6 Million Da | 20mg/2ml of 1% solution hyaluronate | 1/3 | 26 weeks | Non-prescription nutraceuticals (e.g., glucosamine, chondroitin), topical analgesics, and nasal or inhaled corticosteroids | Report mainly focused on Musculoskeletal and Connective Tissue AEs. Any, Withdrawals, Severe and serious AEs also reported. No detail for others | Yes | Author contacted with no response |
| Atchia 2011 [74] | Hip | IA HA: 69 ± 9 IA SA: 70 ± 10 |
NA (Non-animal stabilized HA, Durolane) | NA (a high molecular weight hyaluronan) | 3ml/60mg | 1/1 | 8 weeks | There were no restrictions regarding medication use | Summary/Not detailed | No | Yes, data sent by the author as number of AEs, and not frequencies; not adequate for M-A. |
| Chevalier 2010 [75] | Knee | IA HA: 63.6 ± 9.64 IA SA: 62.5 ± 9.17 |
NA [Hylan G-F 20 (Synvisc)] | 6000 kDa (Average) | NA (6 ml intra-articular injection) | 1/1 | 26 weeks | Analgesics/ NSAIDs (with a half-life of 5 h or less for indications other than osteoarthritis pain) | Report focused on target knee AEs | No | No (Author) |
| Day 2004 [76] | Knee |
Mean (Range)
IA HA: 62 (39-79) IA Placebo vehicle: 62 (33-75) |
Avian (extracted from rooster combs) | 6.2 × 105 to 11.7 × 105 Da | 25 mg of sodium HA in 2.5 ml of phosphate buffered saline | 1/5 | 17 weeks | In the results section: Important Codeine compounds and NSAID use in violation of the protocol, but patients not excluded | Summary/Not detailed | No | No (Author) |
| Dougados 1993 [77] | Knee | IA HA: 67 ± 9.7 IA Vehicle placebo: 69.0 ± 10.6 |
Avian (extracted from cock’s combs) | 500-730 kDa | Hyalectin 20 mg (10 mg/ml) | 1/4 | 52 weeks | Any nonsteroidal anti-inflammatory drugs (NSAIDs) and/or analgesics | All AEs seem to have been reported | Yes | Author contacted with no response |
| Henderson 1994 [78] | Knee |
Data for severity group 2.
IA HA: 72.1 ± 1.7 IA Vehicle: 67.0 ± 1.7 |
Avian (extracted from rooster combs) | 500,000 -750,000 Da | 20 mg Hyalgan in 2 ml of sterile buffered saline | 1/5 | 22 weeks | Alternative analgesia or anti-inflammatory treatment (permitted during the follow up but not during the treatment period) | Summary/Not detailed | No | No contact information found |
| Henrotin 2017 [79] | Knee | IA HA: 66.9 ± 10.4 IA SA: 63.0 ± 8.9 |
NA (Kartilage® Cross, a new reticulated HA supplemented with mannitol) | NA | 2.2ml, 16mg/ml HA | 1/1 | 26 weeks | NSAIDs, Topical NSAIDs | Summary of numbers of AEs | No | No (Laboratories VIVACY, France. Data promised but not provided.) |
| Heyworth 2008 [80] | Hand (Basal joint - thumb) | IA HA: 65.0 ± 2.0 IA SA: 64.0 ± 2.0 |
Avian (derived from rooster combs) | NA | NA (1-mL injection of hylan G-F 20) | 1/2 | 26 weeks | NSAIDs (ibuprofen 400 mg every 4–6 h, as needed) | All reported: “No AE observed during the study” | Yes | Author contacted with no response |
| Huskisson 1999 [81] | Knee | IA HA: 65.8 ± 8.8 IA SA: 64.8 ± 9.3 |
Avian (extracted from rooster combs) | 500–730 kDa | 20mg/2ml | 1/5 | 26 weeks | NSAIDs | Summary focusing in local reactions (in the majority of patients); specific reactions reported | No | No contact information found |
| Jubb 2003 [82] | Knee | IA HA: 63.5 ± 9.5 IA SA: 65.0 ± 9.1 |
NA (Hyalgan®) | 500–730 kDa | 20mg/2ml HA | 3/3 | 52 weeks | Free use of analgesics and NSAIDs except indomethacin | Most common AEs (≥ 5%) reported. Only Specific AEs reported (SOC ranking was possible for some AEs) | Yes | No (Fidia Pharma) |
| Kwon 2013 [83] | Glenohumeral joint (shoulder) | IA HA: 66.1 ± 10.7 IA SA: 66.1 ± 11.7 |
Avian (extracted from rooster combs) | 620,000–1,170,000 Da | NA | 1/3 | 26 weeks | Current regimen of pain medications could be maintained but no additional treatment to the shoulder | Report mainly focused on device related AEs. AEs by SOC not reported, but “Any” and “Serious” AEs reported | Yes | Author contacted with no response |
| Lohmander 1996 [84] | Knee | IA HA: 58.53 ± 8.34 IA SA: 58.03 ± 8.44 |
NA (Hyaluronan, Artzal®) | 1000 kDa (Average) | 25mg/2.5ml | 1/5 | 20 weeks | Simple analgesics, in addition to NSAIDs | Summary/Not detailed | No | No (Author) |
| Lundsgaard 2008 [85] | Knee | IA HA: 68.8 ± 6.27 IA SA: 69.6 ± 7.27 |
NA (Hyaluronate, Hyalgan®) | NA | 2ml of Hyalgan, 10.3 mg/ml | 1/4 | 26 weeks | NSAID (inclusive COX-2 selective inhibitors), codeine, and tramadol | No AE (serious, non-serious, local reaction, post injection ‘flares’) reported during the trial. But 1 withdrawal after 2 weeks due to cerebral haemorrhage | Yes | Author contacted with no response |
| Munteanu 2011 [86] | First MTPJ (foot) | IA HA: 53.7 ± 11.3 IA SA: 55.3 ± 11.2 |
NA (Hylan G-F 20, Synvisc) | NA | NA (up to 1 ml of hylan G-F 20) | 1/1 (with an option of a 2nd and final injection at month 1 or 3 if there was no improvement) | 26 weeks | Not clear: “Use of (paracetamol rescue medication) and co-interventions to relieve first MTPJ pain, as secondary outcome” | Summary/Not detailed | No | Author contacted with no response |
| Navarro-Sarabia 2011 [87] | Knee | IA HA: 63.0 ± 8.2 IA SA: 63.9 ± 8.9 |
Obtained from strains of Streptococcus zoopidemicus | 900,000 Da (Average) | 2.5 ml 1% sodium hyaluronate | 4/5 | 174 weeks | Short cycles of NSAID | Numbers of AEs reported, not per SOC frequencies | No | Author contacted with no response |
| Petrella 2008 [88] | Knee | IA HA, DMW: 68.0 ± 6.0 IA HA, LMW: 69.0 ± 5.0 IA HA, HMW: 71.0 ± 9.0 IA SA: 71 ± 8 |
NA | DMW: 580–780 kDa + 1.2 to 2.0 million Da LMW: 500–730 kDa HMW: 6 million Da |
NA | 1/3 | 16 weeks | Analgesics (including NSAIDs) | Summary/Not detailed | No | Author contacted with no response |
| Pham 2004 [89] | Knee | IA HA: 64.9 ± 8.4 IA SA: 64.9 ± 7.7 |
Produced from Streptococcus equus | 1.900 kDa | 25 mg of sodium hyaluronate in 2.5 ml | 3/3 | 52 weeks | NSAIDs | Most commonly seen AEs reported. By SOC report for some SOCs, and only specific AEs for GI | Yes | Author contacted with no response |
| Qvistgaard 2006 [90] | Hip | IA HA: 65.0 ± 14.0 IA SA: 64.0 ± 11.0 |
NA (Hyalgan®) | NA | NA (2 ml HA) |
1/3 | 13 weeks | Usual analgesic consumption (with no other information) | Summary/Not detailed | No | No (Fidia Pharma) |
| Richette 2009 [91] | Hip | IA HA: 60.8 ± 10.2 IA SA: 59.5 ± 12.6 |
Obtained from Streptococcus fermentation | 900,000 Da | NA (2.5 ml of HA) | 1/1 | 13 weeks | NSAIDs or step 2 analgesics | Summary: All AEs not reported. Some specific (probably related to treatment) AEs reported | No | No (Author) |
| Strand 2012 [92] | Knee | IA HA: 60.9 ± 10.24 IA SA: 60.3 ± 9.97 |
Avian (Chicken combs) | NA | 30 mg HA in 3 ml | 1/1 | 13 weeks | NSAIDs, herbal therapies, oral HA, glucosamine, chondroitin sulfate, minocycline and short-acting oral opiates | Focus on TRAEs: per SOC results nor reported; “Any” and “Serious” AEs frequencies provided. | Yes | Author contacted with no response |
| Wobig 1998 [93] | Knee | IA HA: 60.0 ± 2.0 IA SA: 64.0 ± 2.0 |
NA (Hylan G-F 20) | NA | NA (2 ml of Hylan G-F 20) | 1/3 | 26 weeks | Steroids, NSAIDs, analgesics, or any other therapy for the treatment of OA | Summary/Not detailed | No | No contact information found |
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, COX-2 cyclooxygenase 2, DMW dual molecular weight, GI gastrointestinal, HA hyaluronic acid, HMW high molecular weight, IA intra-articular, IAHA intra-articular hyaluronic acid, IASA intra-articular saline, LMW low molecular weight, M-A meta-analysis, MTPJ metatarsophalangeal joint, NA not available (i.e. information not provided in the manuscript), NSAID non-steroidal anti-inflammatory drug, OA osteoarthritis, P25–P75 25th percentile–75th percentile, SD standard deviation, SOC System