They pooled results from 400mg-800mg from Ph2 Duet trial 47% vs...

They pooled results from 400mg-800mg from Ph2 Duet trial 47% vs 45% from all cohorts 200mg, 400mg, 800mg). I think they up titrated in the Ph2 also in the 800mg group (starting at 400mg & there was an issue with computer generated randomisation of treatment cohorts in the DUET trial).

There may be a lot of patients who can’t tolerate 800mg & as you said either don’t get up-titrated due to BP or possibly step down to 400mg after a period of time. A 2 year trial is a long period of time to be suffering from AEs vs 8 weeks. 300 patients 1:1 randomisation (so 150 patients on Sparsentan).

The “adaptive” comment was a bit odd, maybe also due to participant retention or renal deterioration into ESKD requiring dialysis over the length of the trial?

The other thing is this trial requires patients to come off SOC (Ibersartan) with a washout period, so these patients will be fully aware of changes to their health, symptoms & feeling of wellbeing.

Looking at it from a patient perspective, if you were struggling along with AEs every day knowing you would be on a trial drug for >2 years that are worse than on SOC, & they were significantly impacting your QOL, knowing your prognosis on eGFR slope, what would you do?

I think this is a very important point in any chronic, progressive disease - QOL & subjective patient data is also important they keep in their trial diaries (standardised questions). Patients may feel perfectly fine on Spartensan, but there is a lot more to clinical trials than just looking at a reduction in proteinuria & I think the AEs in Ph2 Retrophin DUET trial would certainly impact on daily life in affected patients. They may have nasty symptoms anyway from the disease process.

I have re-posted the Retrophin Ph3 trial registration so others can see what you are referring to HS. Ph2 DUET trial has been recently posted, so people can refer back to that. Thanks for sharing the above, very interesting.

https://clinicaltrials.gov/ct2/show/NCT03493685?term=Retrophin&draw=2&rank=1