Norwegian Rituximab study - An update by the Norwegian ME association 2014.11.09

[Adele]

One GP told me that they could axe the study after 12 months if they results were very promising.

I have also been told this. The explanation was that the ethical committee can axe the study if they find that the preliminary results are so good that it is seen as unethical to let the study continue without giving the drug to everyone. It would be very interesting to know exactly how good the results have to be for this to happen.

 

[deleder2k]

I think the dose is the same as at day 0 and 14. It is just called maintenance since it is required to do so to keep the b-cells depleted.

 

[Sherlock]

I have also been told this. The explanation was that the ethical committee can axe the study if they find that the preliminary results are so good that it is seen as unethical to let the study continue without giving the drug to everyone. It would be very interesting to know exactly how good the results have to be for this to happen.

The biggest and most famous study to be halted for efficacy like that is probably the JUPITER trial using an anti-inflammatory drug (statin) versus heart attacks. In which case:

"After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary composite end point by 44%, as well as nearly all of the individual end points—including a 55% reduction in nonfatal myocardial infarction, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of hard cardiac events (a composite of myocardial infarction, stroke, and death from cardiovascular causes)—compared with placebo. The trial was halted by the Data and Safety Monitoring Board."

http://www.nature.com/nrcardio/journal/v6/n3/full/ncpcardio1454.html

 

[Sherlock]

What do they mean by:

Maintenance at 3, 6, 9 and 12 months

Maintenance sounds different than treatment.

One difference: let's say that each B-cell gets coated with up to 25,000 RTX antibodies (because a typical B-cell has about 25,000 CD-25 proteins on it). That uses up the infused antibodies at a fairly fast rate.

But once the B-cells are eliminated from circulation, the antibodies from followup maintenance infusions will be left to be circulating around, waiting to attach to any new B-cells that turn up. They can therefore last for several months, almost as if on guard duty.

But still, maintenance doses at every 3 months is more frequent than is used for lymphoma and CLL - which IIRC is generally once per year. It's known that RTX can stop working, after all... just like overused antibiotics can become useless.

 

[Adele]

The biggest and most famous study to be halted for efficacy like that is probably the JUPITER trial using an anti-inflammatory drug (statin) versus heart attacks. In which case:

"After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary composite end point by 44%, as well as nearly all of the individual end points—including a 55% reduction in nonfatal myocardial infarction, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of hard cardiac events (a composite of myocardial infarction, stroke, and death from cardiovascular causes)—compared with placebo. The trial was halted by the Data and Safety Monitoring Board."

Thank you @Sherlock that is very interesting. That drug demonstrated around 50% effect and was halted for efficacy. Wonder what will happen in about a year if Rituximab shows to have 60-70 % effectiveness also in this phase III trial.

 

[deleder2k]

I hope so. But would it be accurate to say they are less likely to halt a positive study on ME compared to a study which shows reduced heart rate risk, and therefore lowered mortality rate?

 

[Jonathan Edwards]

I don't think it is likely that with encouraging results the study would actually be closed. All that may happen is that unblinding may be allowed at 1 year and an early analysis made. That would not normally reduce the amount of follow up information on relapse and re-treatment being gathered.

 

[Adele]

I don't think it is likely that with encouraging results the study would actually be closed. All that may happen is that unblinding may be allowed at 1 year and an early analysis made. That would not normally reduce the amount of follow up information on relapse and re-treatment being gathered.

That would of course be the very best solution! That would then probably both give patients earlier access to the drug which works at the same time as the study of the long-term results would continue. Now I already know what my Christmas wish for 2015 is

 

[deleder2k]

I don't think it is likely that with encouraging results the study would actually be closed. All that may happen is that unblinding may be allowed at 1 year and an early analysis made. That would not normally reduce the amount of follow up information on relapse and re-treatment being gathered.

Does that mean that non-responders will exit the study?

 

[greeneagledown]

@Jonathan Edwards -- The dosing schedule for the phase 3 study that the Norwegians just started is 0 and 2 weeks, then 3, 6, 9, and 12 months. What is the rationale behind trying such frequent doses? I thought it generally took at least 6 months for B-cells to really start coming back in earnest following a dose of Rituximab; isn't that why every 6 months is the most often that Rituximab is currently approved for use? Or can there be significant recovery in B-cell population even before the 6-month mark following a dose of Rituximab? If recovery of B-cell population prior to six months after the initial dose is very small, why would having extra doses at 3 and 9 months (as opposed to just every 6 months) potentially improve the treatment?

@deleder2k, do you have thoughts on this?

 

[Jonathan Edwards]

@Jonathan Edwards -- The dosing schedule for the phase 3 study that the Norwegians just started is 0 and 2 weeks, then 3, 6, 9, and 12 months. What is the rationale behind trying such frequent doses? I thought it generally took at least 6 months for B-cells to really start coming back in earnest following a dose of Rituximab; isn't that why every 6 months is the most often that Rituximab is currently approved for use? Or can there be significant recovery in B-cell population even before the 6-month mark following a dose of Rituximab? If recovery of B-cell population prior to six months after the initial dose is very small, why would having extra doses at 3 and 9 months (as opposed to just every 6 months) potentially improve the treatment?

@deleder2k, do you have thoughts on this?

This is a good question. The problem is that we do not understand the B cell recovery process at all. In general significant numbers of B cells do not re-appear until 6 months, but there are sometimes signs of autoantibody regeneration as far back as 4 months. There are about five B cell subcompartments to consider and we do not know how sensitive they all are to local rituximab levels.

In simple terms, giving one dose of rituximab every 3 months rather than two doses every 6 months is quite a sensible way to try to 'keep the lid on' any re-emergence of bad B cell activity. If the idea is block all re-emergence then keeping a steadier level makes sense. At some point you probably need to give the immune system a rest and allow B cells to return but there is evidence from other autoimmune diseases that suggests you might hold remission if you block the process for 18 months to 2 years rather than just 6 months at a time.

 

[deleder2k]

@deleder2k, do you have thoughts on this?

This is from their application to the Research Council of Norway.

You could also take a look at a graph from the double blinded study which shows if or when patients relapsed. One can also see their B-cell count at the same time: http://www.plosone.org/article/fetc...ournal.pone.0026358.g003&representation=PNG_L

 

[Anne]

I'm sure this has already been posted here somewhere, but here goes:
The Most Important ME/CFS Treatment Trial Ever Begins: Fluge and Mella on the Rituximab Trial
http://www.cortjohnson.org/blog/201...rial-ever-begins-fluge-mella-rituximab-trial/

 

[greeneagledown]

@deleder2k -- Do you know how recruiting is coming along for the phase 3 study? I assume it isn't full yet. I hope they don't run into problems filling it up; I know that's been the case with a lot of CFS studies, although that seems unlikely here.

 

[alex3619]

That drug demonstrated around 50% effect and was halted for efficacy.

Effect size is a big thing. Fifty percent improvement is huge for any treatment. If we can get nearly all patients nearly all the way to well with Rituximab we could get an early present and have it deemed a success long before the trial data is officially due to be released.

The point of a large and long trial is to eliminate as much bias as possible. Huge effect sizes do the same thing.

PS I am unsure of what admin issues there are with blinding and unblinding data.

 

[deleder2k]

@deleder2k -- Do you know how recruiting is coming along for the phase 3 study? I assume it isn't full yet. I hope they don't run into problems filling it up; I know that's been the case with a lot of CFS studies, although that seems unlikely here.

Think they had 1500 requests to opt-in, and 152 spots available - no chance they won't fill it up. People are going crazy to participate.
I think one or two of the study centres have included their slot of patients. From what I've heard everyone needs to be done in May.

 

[Joolz]

People are going crazy to participate.

At least they'll fit 20 patients or so into the cyclo study And I don't know how many of the 1500 patients fulfil the Canadian criteria, and how many were sorted out for other reasons.

From what I've heard everyone needs to be done in May.

That's what I heard, too, but I also heard that they haven't come very far at all in Northern Norway? What happens if they're not done by end of May?

 

[deleder2k]

At least they'll fit 20 patients or so into the cyclo study And I don't know how many of the 1500 patients fulfil the Canadian criteria, and how many were sorted out for other reasons.
That's what I heard, too, but I also heard that they haven't come very far at all in Northern Norway? What happens if they're not done by end of May?

I don't know. I think we're talking about 32 patients or something. Lets hope they can speed things up.

 

[greeneagledown]

Assuming they can hit their target of having the last patient get the first infusion no later than the end of this May, it seems reasonable to expect a publication by the end of 2017... which is pretty exciting.

 

[Sasha]

@deleder2k - probably the wrong thread for this, but do you know how much patients and supporters (not government) raised for the Norwegian rituximab work?