INTERCEPT'S STUDY CURIOSITIES (by Gery DIVRY)

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May the 19 2015,  Intercept annouced a pivotal study on NASH named REGENERATE 

They described the the design of the study as conforming the wishes of the FDA and the EMA ..


«  In accordance with harmonized advice from the FDA and European Medicines Authority (EMA),the Randomized Global Phase 3 Trial to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment (REGENERATE) has been designed as a double-blind, placebo-controlled pivotal Phase 3 clinical trial expected to enroll up to approximately 2,500 patients and assess the potential benefit of OCA treatment on liver-related clinical outcomes. The trial will include a pre-planned interim histology analysis after 72 weeks of treatment in approximately 1,400 patients which is intended to serve as the basis for seeking U.S. and international marketing approvals of OCA for the treatment of NASH patients with liver fibrosis. »

 

The main parameters of the design were :

A 5 year study with intermediate point at 18 month.

3 arms , and 2500 patients

This design with 2500 patients was confirmed in the first publication of the design on clinicaltrials.gov 

in July in their FORM Q10  they wrote 

Page 20  and page 17

"We completed regulatory discussions regarding the Phase 3 trial design for our clinical program for OCA in non-cirrhotic NASH patients with liver fibrosis in June 2015 and plan to initiate the trial in the third quarter of 2015. »



the Sep 28 2015, they announced the Initiation of the REGENERATE TRIAL with modified parameters.

"REGENERATE has been designed as a double-blind, placebo-controlled Phase 3 clinical trial expected to enroll approximately 2,000 NASH patients at up to 300 qualified centers worldwide and assess the potential benefits of OCA treatment on liver-related and other clinical outcomes. The trial will include a pre-planned interim histology analysis after 72 weeks of treatment in 1,400 patients, which is intended to serve as the basis for seeking initial U.S. and international marketing approvals of OCA for the treatment of NASH patients with fibrosis. Two co-primary endpoints will be assessed in the interim analysis: (i) fibrosis improvement with no worsening of NASH and (ii) NASH resolution with no worsening of fibrosis. »

The study design was modified silently on clinicaltrials.org only the 7 of october 2015 

If the first design was established In accordance with harmonized advice from the FDA and European Medicines Authority (EMA) , what parameters changed  to allow a 20%  patients population reduction of the study with no any explanation?

In their new design, will they allowed to count as cured (NASH reversion) patients with no NASH at the begenning of the study ?


By analyzing the tables in FLINT’ Appendix  published in the Lancet I was surprised.

Intercept announced a resolution of NASH 22% vs 13% (not statistically significant), but equal to that of the same population GENFIT NAS> 4 theoretical . 

I was working to see how far from statistical significance the result was and so, I analyzed this beautiful Table supposed to illustrate the OCA resolution of NASH

In this Figure The 'baseline category column represent the state of the patients at the beginning of the study, we can see that in the OCA group, 8 patients had no NASH but NAFLD, the placebo group had 11 patients in the same case. So 19 patients in total, equivalent to 10% of the sample , was out of the recruitment criteria, to have a NASH.

Most disturbing is that to calculate the %of NASH reversal, they count the patients who had NASH and does not have NASH anymore at the end of the study.. Normal.

But they also count those who did not have NASH at start and did not changed their state at the end of the study , which is less logical. (circled in red) 

Why ?

It seems that the figures should therefore be 18% vs 7% insignificant , or if we exclude patients without NASH, 19% vs 8% ...

The resolution of NASH in 22% vs 13% placebo OCA announced by intercept seem questionable even if one can not take into account because of its lack of statsistique significance (p> 0.05)


My question is : who checked the study results published by intercept and will they use the same method in their phase 3 ??




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