seems to be a problem with replying on HC- my previous 2...

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MongooseMan

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27/02/24

12:02

Post #: 72617319
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Originally posted by butcherano: ↑

Hotcopper reply function on the blink again so struggling to reply to your original post @MongooseMan (screenshot for reference and my comments below).

Just coming back to the statistical powering of the trial. What this is telling us is that the company is hoping to see >= 1.68 ml/min/1.73 m2 per year improvement on the eGFR slope (annualised after 2 years). Based on previous data from the company for the relationship between proteinuria reduction and eGFR slope - this would equate to a 30% reduction of PCR. Seems ambitious but must be based on some confidence from the company that it’s achievable.

But I’m not sure that the criteria to determine the 80% power is necessarily the specific criteria for success or failure of this endpoint. I’d be interested to know from a statistician what the powering would look like for achieving >= 1.1 ml/min/1.73 m2 per year improvement on eGFR slope in terms of the probability of success with this patient size. This would equate to a PCR reduction of 20% (or a total of > 40% including the contribution from Irbesartan) which is more likely to be the endpoint criteria and aligns with the criteria for achieving FPRE. This seems to be the consensus for this endpoint from what I’ve researched.

Sparsentan didn’t meet their eGFR slope endpoint for a number of reasons including higher than expected reduction of PCR in the placebo group (and potentially the corresponding impact this had to eGFR slope). Although from Week 6 to 104 they showed a better improvement on Sparsentan than from day 1 (0.9 ml/min/1.73m2 difference from placebo) which was promising. Maybe the trial design had something to do with this result. Because Travere were essentially comparing two options for the same mechanism of action (both ARB's) there was a washout period at the start where they weren’t taking anything. So I’m wondering if being randomised back onto Irbesartan after the washout period may have actually amplified the benefit because of the fact that they stopped taking it for a period of time. The actual baseline readings that were being used after washout may have been misleading and caused higher relative differences? This is something that won’t be an issue based on our trial design. The other thing to note is that there’s eGFR data for Sparsentan from other trials that showed significant improvement to eGFR slope. Albeit for other indications but it still shows the ability for Sparsentan to improve eGFR slope and might add more weight to the issue with the Duplex trial being more related to trial design and not necessarily the efficacy of the drug itself.

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seems to be a problem with replying on HC- my previous 2 responses are to you @@butcherano

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