A lurker here. For anyone interested in a non-holders...

A lurker here. For anyone interested in a non-holders perspective regarding the trial results – and ensuring debate – with some experience in clinical trials (although I hasten to add not RA trials).

When I first read the announcement I thought there was much to be positive about. I think the problems with interpreting the results – start with the study design. As a phase 11a study it is more about dosing than it is about efficacy (11b). Which makes the ACR20 a strange choice as the primary outcome measure – when it is known that this measure is sub-optimal for dosing studies – and the ACR-N is more sensitive to change – and arguably more appropriate. (As outlined in the Siegel paper posted on the forum a while back).

The choice of the non-responder group (on the gold standard tx) – I think made a high placebo response more likely – which is acceptable for a 11a study but less desirable for a 11b study – which many holders appear to be interpreting this trial as.

It is positive that many secondary measures moved – particularly the sf-36. Would have liked to have seen this by SF sub-scales – and the secondary outcomes reported with effect sizes (big difference between statistical and clinical significance). Might be enough data in the first report to derive these (haven’t looked). The dose response relationship is very encouraging.

It would be useful reading the protocol paper (if one was published) or the Ethics application (if available) to understand the thinking behind the study design – specifically around power and sample size. It would also interesting to know if the pharma had a say in the design. I suppose the failing of the study is that as dosing study limited information seems to have been provided – other than finding out more work needs to be done to get this right. Seems a pretty expensive way of finding this out?

I know nothing of the politics behind all this – but was a bit taken aback by the Directors “negative” view of the results expressed in the letter. I’m all for results not being “sexed up” – but the questions raised deserved a better response than “your all idiots”. If I were a shareholder I think my response would be that any idiot can produce a non-significant result – the cleverness (and why your paid the big bucks) comes in getting a significant result. Given the board still express confidence in Xtoll – at some level – either shortcomings in the trial or manner in which the results have been presented don’t line up.

In terms of the relative importance between primary and secondary outcomes debate - this looks pretty arbitary to me. There could have been good arguments for a number of the secondary outcomes as the primary outcome. None of the secondaries look like mediating variables. The fact that a number of these moved - in some nice clusters - suggests these were more sensitive to change. The fact some didnt could simply be due to the fact that studies are usually not powered for secondary outcomes.

Watch for the conference paper – usually conferences aren’t interested in late breaking null results – you might get a better picture from this – compared with the companys view of asx announcements that seem to invoked a bit of paranoia.

All imo – and there are some good posters here who know the history much better than me – and obviously have some experience in clinical trials – so happy to be corrected on any of these observations.

Good luck Southoz.