Phase III Rituximab Trial - News

Scarecrow said:
The outcomes are specified in advance to avoid cherry picking the data (PACE anyone?). I'm trying to find the protocol. I know someone put it up on PR but I can't see it yet.
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It's here https://clinicaltrials.gov/ct2/show/NCT02229942
Primary Outcome Measures:
  • Fatigue score, selfreported. [ Time Frame: Course of Fatigue score during 24 months follow-up. ]
    Selfreported Fatigue score is registered every second week, as the mean score for the four symptoms: "Post-exertional malaise", "Fatigue", "Need for rest", "Daily functioning" (scale 0-6). Mean Fatigue scores for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are recorded for each patient. These data are used for statistical analysis. The difference in course of Fatigue score during 24 months follow-up, between the rituximab and placebo groups, will constitute the primary endpoint.

    Overall response is recorded as the effect on CFS/ME symptoms during 24 months follow-up. The overall response is not predefined to a specific time interval, but is defined as mean Fatigue score at least 4.5 for at least 8 consecutive weeks for moderate response, and mean Fatigue score at least 5.0 for at least 8 consecutive weeks for major response. Single response periods and the sum of response periods during 24 months follow-up will be recorded.


Secondary Outcome Measures:
  • Short Form-36 (SF-36) [ Time Frame: Changes in SF-36 scores during 24 months follow-up ]
    SF-36 (ver 1.2) are selfreported by patients at baseline, and at 3, 6, 9, 12, 15, 18, 21 and 24 months follow-up. Changes in Physical health summary score, Physical function, and "Mean of five subdimensions" (Physical function, Bodily pain, Vitality, Social function, General health) are recorded. The difference in course during 24 months follow-up, between the rituximab and placebo groups, will constitute secondary endpoints.

    Also, the difference between rituximab and placebo groups, in changes from baseline to recording at 18 months, for Physical health summary score, Physical function, and "mean of five SF-36 subdimensions", constitute secondary endpoints.


  • Physical activity (Sensewear armband) [ Time Frame: Analyzed at baseline and at interval 17-21 months ]
    The patients' physical activity level, in a home setting for 7 consecutive days, is recorded using Sensewear armbands, with registration at baseline and repeated in the time interval 17-21 months follow-up. Changes from baseline to analysis during the time interval 17-21 months, for mean number of steps per 24h, maximum number of steps per 24h, mean duration per 24h with activity level at least 3.5 METs, max duration per 24h with activity level at least 3.5 METs, are recorded. The difference between rituximab and placebo groups will constitute secondary endpoints.

  • Self-recorded "Function level" [ Time Frame: Course during 24 months follow-up ]
    Self-recorded "Function level" (scale 0-100, compared to healthy state, according to a set of examples) are registered every second week. Mean "Function level" for the time intervals 0-4, 4-8, 8-12, 12-16, 16-20, 20-24 months are calculated. The difference in course of "Function level", between the rituximab and placebo groups, constitute a secondary endpoint.

    Also, the differences between the rituximab and placebo groups, for changes in selfreported "Fatigue score" and in selfreported "Function level", calculated from baseline to the mean value during the time interval 16-20 months, constitute secondary endpoints.


  • Fatigue Severity Scale [ Time Frame: 24 months ]
    Fatigue Severity Scale (FSS) is self-recorded at baseline and at 6, 12, 18, 24 months. The difference between the rituximab and placebo groups, in changes in FSS from baseline to 18 months follow-up, constitutes a secondary endpoint.

  • Clinical response duration [ Time Frame: During 24 months follow-up ]
    Clinical response periods, defined as consecutive self-recorded Fatigue score at least 4.5 (scale 0-6) for a minimum of 8 weeks, during 24 months follow-up, are recorded.

    The difference in the longest consecutive clinical response period, between rituximab and placebo groups, constitutes a secondary endpoint.


  • Sustained clinical response at 24 months [ Time Frame: Assessment at 24 months ]
    The difference between rituximab and placebo groups, in fraction of patients with sustained clinical response (defined as Fatigue score of at least 4.5) at 24 months, constitute a secondary endpoint.

Other Outcome Measures: Toxicity and side-effects [ Time Frame: During 24 months follow-up ]
Toxicity and side effects will be recorded throughout 24 months follow-up, as specified in the protocol.
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One good thing is that I do not think that this should be used against us - fortunately lots of patients stayed relatively cautious. [edit: Not that this will necessarily stop unscrupulous spin - but at least we didn't give them an open goal.]

It's obviously disappointing, as this seemed like our best chance of an imminent treatment, but it looks like we're just going to have to keep slogging on. Better to have rigorous research that reveals a disappointing result than poorly conducted research that leads to a misleading positive result. Very grateful to Mella and Fluge for all the work they've put in, regardless of the result.

IMO: At the moment the priority for us should be to keep pushing for high quality research, keep fighting against poorly conducted research with spun results. Maybe we'll get lucky with something else, but our best shot for genuinely useful interventions is to do what we can to pick apart the continuing flow of junk-science imo.
 
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Statement from Invest in ME


For us we have invited the Haukeland team to Norwich to discuss the way forward.

We remain positive. Another setback, another day.

We have already been in discussion with our advisors and with the Norwegian team and we will meet to clarify the best way forward in the near future with our major funder and researchers.

We still have much good research being funded and being planned and feel our stategy is, and will pay off and lead to most rapid route to finding cause(s) of ME and effective treatments.

In another age, and in a struggle which has some parallels to that which is forced upon people with ME, these words strike a chord -


“ We must accept finite disappointment, but never lose infinite hope. ”

- Dr Martin Luther King
 
Oh dear. Hope for this as future treatment had been keeping going in the back of my mind too (I don’t mean in a dramatic way, I’m upset not suicidal). But potential treatment around the corner takes away the dread of unrelenting crap ness. Literally :cry:

We should probably keep an eye out for pwme friends over the next week or so. Chase up anyone who isn’t online as much etc. I imagine I’m not the only one rituximab had this psychological function for.

Esther12 said:
Better to have rigorous research that reveals a disappointing result than poorly conducted research that leads to a misleading positive result.
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There is this. I appreciate that they aren’t spinning this into a victory it isn’t. It shows integrity.

What I want to know is what is so different from stage two? Is it a different criteria? Different outcome measures?
 
Thanks for posting the news!

This is quite disappointing. :(
Although there were hints.

I also wish the very best for the researchers - I imagine this outcome may be frustrating for them, too - and I hope they will keep on doing real science on ME.
 
Jenny TipsforME said:
What I want to know is what is so different from stage two? Is it a different criteria? Different outcome measures?
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The primary outcome measure certainly looks very similar to the method they used for the phase II.

I'm not (yet) despondent about the news because all we know until publication is that rituximab "failed to be clinically effective" (quoting Marky90 at PR). It doesn't mean that rituximab is not effective for everyone with ME/CFS. We'll need to wait and see just how many people responded, who didn't and who got worse.

We always suspected that ME/CFS comprised several diseases. Clearly, phase III failed to reproduce the high responder rate in the earlier trials but many people always thought that would be too much to hope for. (Not me, I'm stupidly naïve and optimistic!)
 
I'm assuming that there will still be responders, the question is how many.

What this phase III news means in practical terms is that we'll have more accurate knowledge of the proportion of responders than we did before. It means that the price of rituximab per response has just gone up. In the absence of being able to predict a response, the odds have worsened.
 
Kalliope said:
Wasn't the dosages of Rituximab in the phase III trial a tad smaller than in the previous ones? Don't know what importance that has, though.
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Yes, you're right. The follow up doses were fixed at 500mg, rather than being 500mg/m2 up to a maximum of 1000mg. Also the maintenance period was 'stretched out' slightly.

Phase II 'Materials and Methods
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129898
Treatment schedule and follow-up
The patients were given rituximab infusions in the outpatient clinic at Department of Oncology, Haukeland University Hospital. The induction treatment, rituximab 500 mg/m2 (maximum 1000 mg), diluted in saline to a concentration of 2 mg/ml, was administered twice with two weeks interval, with nurse surveillance and according to local guidelines. The patients then received rituximab maintenance infusions, 500 mg/m2 (maximum 1000 mg) at 3, 6, 10 and 15 months follow-up. All patients were given oral cetirizine 10 mg, paracetamol 1 g, and dexamethasone 8 mg prior to infusion. The two pilot patients received only one rituximab induction infusion, with the sixth (last) infusion at 18 and 19 months (instead of 15 months) respectively.

According to protocol, the planned 10 and 15 months infusions could be omitted if there were no signs of clinical response at the 10-months visit.

The present open-label phase II study also had exploratory elements, aiming to gain knowledge on dose-response relationships for proper design of a later randomized phase III study. Therefore, by December 2011 an amendment was submitted to and approved by The Regional Ethical Committee; for patients with slow and gradual improvement after 12 months follow-up including five rituximab infusions, up to six additional rituximab infusions could be given with at least two months intervals. No other intervention should be given during follow-up. After infusions, the patients attended the outpatient clinic at 20, 24, 30 and 36 months, for assessment of the clinical course of their disease, including delivery of self-reported symptom forms. Most of the patients including those still in ongoing remission at the end of follow-up, have been assessed at regular intervals even after the study period.
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Phase III protocol
https://clinicaltrials.gov/ct2/show/NCT02229942
Assigned Interventions
Drug: Rituximab


Induction with two infusions two weeks apart, rituximab 500 mg/m2 (max 1000 mg).

Maintenance with rituximab infusions (500 mg fixed dose) at 3, 6, 9 and 12 months.

Other Names:
  • Rituxan
  • Mabthera
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Dechi said:
That made me cry. I am so depressed from this terrible outcome.
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Sorry to bring you down! I'm basically middle-aged now, so it's not saying much. I looked back and thought my first post on this look irritatingly calm and positive about the bad news, so thought I should add in a little heart-ache too.

It's bad news, but we're still in a better position with research than we were five yeas ago. We're just going to have to keep slogging away.
 
I think we need to allow ourselves to feel the disappointment but this quote in the Invest in ME response is one to remember

we-must-accept.png


One day the research will get there but ok to :cry: today because it isn’t imminent

Re different phases:
Do we think there’s a placebo/demand characteristic type thing going on? If they were expecting positive results up until the unblinding it perhaps points to that? Did people in the placebo arm also respond?

But I always thought placebo was unlikely in the first two phases because of the weird delayed response, which I don’t think participants would know to expect. Need to wait for more info.

I guess my question is: does this work at a biological level for fewer pwme than we hoped OR was it a false positive that it worked in the previous studies?

Will other studies now not go ahead? @Jonathan Edwards @Jo Best
 
I have suffered from ME for over 20 years. It was first when Fluge/Mella published their small Rituximab-trial back in 2011 that I started to develop a sincere hope for a better life - to receive a cure, or at least treatments, sometime in the future.

The news today are disheartening indeed, but there is so much going on now when it comes to ME-research, that even though I am disappointed of course, my hope at least isn't shattered.
 
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