PHASE III ‘REGENERATE’ RECRUITMENT !  
A REASON OF HOURS ?

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From times, I thought that the lack of news on the recruitment of the INTERCEPT phase 3 study  'REGENERATE ‘ had to have a reason


Beyond the extremely rigorous process in place this time for the selection of patients (double reading biopsies first centralized by region, and centralized worldwide) which will inevitably lengthen the process, there is a reason that could explain the slow recruitment .


As we have seen, the disease specialists and field hepatologists have all found that the main cause of death of their NASH patients were cardiovascular.

During one presentation of NASH performed by Dr. Manal Abdelmalek, renowned hepatologist Duke university, which was one of the first to publish on NASH in 1995, she strongly emphasizes this point (watch the video).

Intercept as part of its post hoc FLINT studies, had shown that patients who began treatment with statins during the study, had their LDL cholesterol fall below its value from the beginning of the study. As against those who were not on statins or who had already established statin therapy prior to the study all had their LDL up by 10% taking the OCA.

Intercept had concluded that combining the OCA with a statin, it would nullify the negative effect of the OCA on cardiovascular risk. They even launched a clinical study to demonstrate it.

The problem is that NASH patients mostly have a proven cardiovascular risk and that their physician did not wait for Intercept prescribe their patients a treatment with statins. In fact, over 50% of patients in the FLINT study were on statins  at endline.

Ongoing clinical FLINT study , 26% of patients started a treatment of statins  in OCA arm , contrary to the established rules which we want does not modify the conditions of the study, during the study, by taking medication that may interfere with the results, is a very interesting sign.

This reveals that, despite the fact that the patient was included in a clinical trial, his attending physician was sufficiently alarmed by the rise of cholesterol induced by OCA that he preferred to prescribe treatment in spite of the current study.

That makes sense, the life of his patient is more important than the respect of any study protocol.

But here, it seems that the protocol of the FLINT study was not so demanding that, as these patients have started another treatment, they still remained integrated in the study and were included in all results, which minimized stastistiquement the rise of cholesterol observed at endpoint, which is frankly borderline ..

This review is in the public square, and one can imagine that now, Intercept will have to show rigor on the protocol of the Phase 3 .. This means patients with stable treatment before the study, and no treatment modification during study.


My opinion is that this is a big problem for the recruitment delays in REGENERATE study.

Indeed if a practitioner following a candidate patient is informed of increased risk of cardiovascular risk related to study what may be his position?

To advise his patient not to participate in this study, ie, knowing that once the study began he may not prescribe corrective treatment, or to anticipate and put his patient on statins preventively.

But the REGENERATE protocol provides that the patient must have a stable dose of any medication in order to participate in the study. In the design of REGENERATE published on clinicaltrials.gov, they do not specify for how long the treatment should be stabilized before the reference biopsy to be considered stable.

By cons, we can recover this time, given on the design of the GENFIT study RESOLV'IT , so .. 6 months before the initial biopsy ..

This is very restrictive, since it involves placing the patient on a stable dose of preventive statin, or if he was already under statin, modify its prescription by increasing it, six months before you can make an initial biopsy, which is only the beginning of the recruitment process.

In addition, the practitioner can not know if the patient will be under placebo or not and therefore, if this is over-medication is not made for nothing, with the induced risks  .. not easy to make a choice.

In this regard, the rise of cholesterol is so obvious and systematic under OCA, it could be a condition for the disappearance of the 'double-blind', a practitioner who would not see the patient's cholesterol rise, could highly doubt that it is treated with a placebo ..

All this could be one reason for the slow Intercept recruitment process, and this hypothesis, which is my own, will probably be confirmed when we will see the rate, probably very high, of patients treated under statins at baseline.

We'll have to monitor any announcement of Intercept on this recruitment.



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