In the present randomised, double-blind, controlled trial in over 400 knee osteoarthritis patients, three-weekly HA intra-articular injections decreased moderate to severe pain after 6 months by up to 50% of baseline values. Joint function improved to a similar extent and there were over 65% treatment responders on average with the two preparations used. The intermediate MW HA formulation GO-ON was not inferior to the reference low MW preparation Hyalgan on the WOMAC pain subscale score, but was also statistically superior on this primary and on most of the secondary outcomes as predetermined by the statistical analysis plan.12
While GO-ON tended to exhibit a trend for a better pattern of response throughout the study, both treatments behaved similarly well over the first month, when most of the therapeutic gain was observed, and during the first 3 months following the injection course. Afterwards, the benefit obtained with the low MW product tended to plateau, as acknowledged with most HA preparations,9
while there was a slight continuous improvement with GO-ON, ie, a more pronounced carry-over effect resulting in a statistically significant superiority on most outcomes after 6 months.
The primary endpoint was the change from baseline in the WOMAC pain subscale score, which displayed an extent of improvement similar to global knee pain VAS. The statistically significant ITT differences between treatments after 6 months were 4.5 and 6.4 mm, respectively, ie, below the minimum perceptible clinical improvement, usually set at approximately 10 mm22
and that was used to define the non-inferiority margin of 9 mm in this trial. Therefore, the clinical relevance of this statistical superiority is uncertain and it cannot be excluded that it is due to chance. However, the effect size ranged between 0.21 and 0.26 for the two pain endpoints, representing a small albeit clinically relevant difference. Moreover, there was a significantly higher proportion of OARSI/OMERACT responders after 6 months with GO-ON (73%) than with Hyalgan (58%), ie, a 15% difference that is beyond the accepted minimum clinically relevant improvement. The OARSI/OMERACT criteria require high improvement in pain or function (≥50% with absolute 0–100 change ≥20), or a moderate improvement (≥20% with ≥10 absolute change) in two out of pain, function or PGA, thus representing a real clinical improvement.18
Notably, there were significantly more OARSI/OMERACT responders with GO-ON already at the 12-week endpoint, as a prelude to the better carry-over effect that was then fully substantiated after 6 months. Similar proportions and differences in response rates were observed for patients reaching the MCII19
on pain and function after 6 months. Moreover, approximately 60% of patients achieved a PASS20
with GO-ON, with a significant difference compared with Hyalgan for function, but not for pain. PGA provided a slightly lower degree of improvement, without differences between treatments in absolute terms and as MCII, but with a more than 15% significantly higher proportion of patients reaching PASS with GO-ON.
A favourable feature of the present trial is that it assessed knee osteoarthritis symptoms through several different measures, providing a complete evaluation. Beside all WOMAC subscales showing a significant advantage for the intermediate MW product, the Lequesne index resulted in an effect size of 0.36 in favour of GO-ON. In addition, pain was also assessed by the new ICOAP index;17
interestingly, patients had slightly more severe baseline values for ‘intermittent’ pain, in which the two treatments displayed a similar efficacy, while GO-ON was better than Hyalgan on the slightly less severe ‘constant’ pain.
This study also has some limitations. First, there was no placebo comparison. This might have been an issue in the case of results limited to non-inferiority, given the debated efficacy of HA in general.9
However, as GO-ON was statistically superior to the low MW product and most of the differences were clinically relevant, this might represent sufficient evidence of efficacy. Moreover, ethics review boards might have raised ethical concerns in using intra-articular saline as a placebo when HA injections are now widely prescribed in knee osteoarthritis.
Second, it was not possible to provide identically appearing test and comparator preparations: the commercial preparations had to be used for obvious reasons, after appropriate packaging, and their effects may also differ given the different injected volumes. On the other hand, double-blind conditions were ensured by nominating at each site an ‘injector’ and a blinded ‘assessor’ investigator, while avoiding the patient's visual access to the injection field. Despite these difficulties, which are standard practice in these kind of trials, there was no evidence of broken double-blindness for any patient, reinforced by the strict assurance of adequately concealed random allocation by the interactive voice response system.
Third, this was a regulatory trial that was therefore industry-funded. Compared with non-industry-funded trials, sponsored studies more often yield results in support of the sponsor's drug.27
To avoid any potential allegations, an independent steering committee (FB, XC, FR, EM) supervised the trial design and study conduct, participated in blind data review meetings before database lock and provided binding recommendations for data management, finally accessing all results.
A fourth limitation was that the present trial only compared the intermediate HA product GO-ON with the reference low MW preparation, but not with a higher MW, cross-linked, formulation. While former studies suggested that high MW HA might have greater efficacy,4
in a recent meta-analysis11
showing that HA has more prolonged efficacy than intra-articular corticosteroids in knee osteoarthritis, five of the seven considered studies (and the only two high-quality trials) were performed with the low MW HA product used as reference in the present trial. Corticosteroids had a superior analgesic effect over the first 2 weeks, as expected, but from 8 weeks onwards and in particular 6 months after treatment HA had better pain control, with an effect size up to 0.39. Another meta-analysis10
found no evidence of a clinically relevant benefit of hylan compared with lower MW HA preparations, and a recent trial concluded to the non-inferiority between another intermediate MW HA and hylan G-F20.28
Actually, a study of single intra-articular hylan injection showed only a modest, albeit significant, benefit versus placebo over 6 months on knee pain, with less OARSI/OMERACT responders than with GO-ON in the present trial and a non-significant difference with placebo.29
A recent study has shown that low MW (50 000 Daltons) HA may have pro-inflammatory activity on chondrocytes, while intermediate MW preparations were neutral in this model of inflammation.30
It is difficult to transpose in-vitro results to humans and to the actual preparations used here, but this may partly explain the efficacy results of the present study, with good safety at the injection site compared with even higher MW products. Indeed, while in a recent trial hylan showed only a trend towards a higher incidence of local adverse reactions compared with placebo,29
previous studies suggested a doubling risk of local AE with the high MW HA preparation compared with lower MW products,10
which may be due to peptide contaminants, formaldehyde, or crystal-induced inflammation. In the present study, GO-ON and Hyalgan were equally well tolerated at the injection site, although numerically more local reactions occurred with Hyalgan than with GO-ON, therefore showing a very good safety of the latter.
In conclusion, this trial shows that the intermediate MW HA preparation GO-ON is effective on knee osteoarthritis symptoms over 6 months after a 3-weekly injection course, and may be more effective than the reference low MW formulation. Further studies are warranted to elucidate the mechanism of this possible superiority and more pronounced carry-over effect and to test whether this selected HA preparation has a prominent therapeutic profile compared with other HA products.