Rituximab study in norway. An application to The Research Council of Norway

[Indigophoton]

...it is a logical to try plasma exchange as initial therapy for this group, followed by Rituximab treatment...

@deleder2k Thanks for all the info you are posting and especially for this: as a very severely affected ME patient you have made my day (all the ifs and buts and maybes nothwithstanding)

Oystein Fluge seems to have so much common sense and compassion. Thank goodness there may be at least one or two individuals in the UK with the same:

What I think is encouraging is that at least one neurological colleague, expert in this field, is ready to take the issue of autoimmunity and immunotherapy in ME seriously and share thoughts.

Regarding,

I constantly ask myself why ME does not seem to be so 'urgent'? There are probably three answers. One is that some of the other conditions include movement disorders that prevent any normal activity or even standing up or sleep.

Hmm, well very severe ME often prevents standing up, sitting up, or even lifting one's arm or raising one's head up off the bed. It can prevent exposure to normal levels of sound and light, which is isolating in the extreme (no conversation, no sunshine, for example.) On top of the disability/loss of function, ME can also make one feel very ill most of the time, resulting in terribly poor quality of life. It's presumably just not obvious enough to others.

@Jonathan Edwards, is it possible that the preliminary work being done for the UK Rituximab trial would advance the search for a reliable marker for the disease, which might help stimulate research and medical activity, or is its aim solely to try to stratify patients into responders and non-responders for Rituximab treatment?

 

[deleder2k]

I am on Propal Retard 180mg, I think that is the same as 3-4x 40mg daily. OI is lower. Not sure about if I have more energy yet.
I haven't tried Cialis yet.
I got an appointment in the first week of August. I think that the doctor could prescribe me gammaglobulines, but I am not sure if I can take it due to the fact I have applied for the Rituximab study. I am in contact with the Rituximab study centers to find out if prior treatment with gammaglobulines excludes one from the study.

Thanks @Indigophoton

One question about the UK rituximab study: I welcome more research towards the "solution" to the problem, but is the study really needed? If everything works out in Norway, shouldn't we be able to treat patients soon? Or is it a requirement from FDA and others that multiple phase 3 studies have been conducted? I know that they're trying to do everything by the book in Norway, because FDA and others could come to inspect the way the study was done.

 

[DanME]

In this study from Raj et al. low doses of Propanolol (20mg/morning) helped patients with POTS lower their heart rate and alleviate their symptoms. However, higher doses (80mg) lowered their heart rate, but made OI symptoms worse. Maybe you could think about lowering your dose.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758650/#!po=2.27273

I took another beta blocker once, Nebivolol 5mg, it lowered my heart rate and stopped the nightmarish palpitations, but over all my OI got worse. So I stopped taking them.

Nice. I am happy for you. What a great chance to get proper treatment. Do you already know, if you are going to be a participant in the study or are you waiting for confirmation?

I think, the more data the researchers are able to generate (even from slightly different angels), the more serious the medical community will take us.
And it is a chance for some patients in the UK to get proper treatment.

 

[deleder2k]

Yes, I could try 80mg which is around 20mg 4 times I day I reckon.


No, no one knows if they're received an invitation to join the study or not. Some say nothing will happen before mid August as the study is not yet accepted by The Norwegian Medicines Agency. Norway is also on holiday. Almost no one works at the moment.

 

[greeneagledown]

@Jonathan Edwards -- Apologies if this is something you've already covered on these forums somewhere. What are your thoughts on the size of the therapeutic effect that patients experienced in the Norway RCT published in 2011? I know that 60% of Rituximab patients were "major responders" as the researchers defined the term. But digging deeper into the data, it looks like only a couple patients had at least one eight-week period where their average self-reported fatigue score was a 5 ("moderate improvement") or higher. A large % of patients had slight improvement for a significant period of time, but very few had even moderate improvement for a significant period of time, let alone major improvement. To me, it looks like the results do indicate that Rituximab is having a statistically significant effect, which would definitely move the science forward, but it doesn't seem like the effect is large enough to make a big difference in the patients' lives. Obviously, if future trials replicate these results, it would still be extremely valuable in terms of figuring out what's going on in CFS, but maybe less valuable in terms of validating Rituximab as an effective treatment.

I guess my question is this: Do you think that adding maintenance doses as was done in the subsequent open-label trial -- at 3, 6, 10 & 15 months -- could not only increase the duration of the effect, as has been discussed, but also possibly increase the size of the effect?

Thanks a ton in advance.

 

[deleder2k]

Latest from the study at Haukeland University Hospital (few months ago): In a randomized phase II study of rituximab two infusions two weeks apart versus placebo in 30 patients with chronic fatigue syndrome, we then completed an open-label phase II study 28 patients received rituximab induction and maintenance therapy, a total of 6 infusions over 15 months.21 patients (72%) had response to defined criteria, 18 patients (64%) had clinical significant improvement in most CFS symptoms.Duration of response within 36-month study period, the mean 108 weeks for 14 major responders and 68 weeks for 4 moderate responders, and 11 are still in response at 36 months follow-up.Side effects: two with allergic reactions, two with upper respiratory tract infections, uncomplicated two with late-onset neutropenia.

I am not sure what the define as a major responder as...

 

[aimossy]

Hi,
I don't know much about NO.
I was wondering if Mella and Fluge are trying to find evidence of their NO hypothesis. Does anyone know about this or can explain this hypothesis in layman like terms or try to?

 

[deleder2k]

@greeneagledown

take a look at this

 

[DanME]

Hi,
I don't know much about NO.
I was wondering if Mella and Fluge are trying to find evidence of their NO hypothesis. Does anyone know about this or can explain this hypothesis in layman like terms or try to?

I ll try.

NO is a volatile gas with a very short lifetime. The body produces it for various functions. It is a neurotransmitter and helps neurons to communicate properly. Furthermore, some immune cells use a toxic form of NO to destroy bacteria. But the most important function of NO is to regulate blood flow. NO is constantly produced inside the walls of all blood vessels and widens them (the biochemistry is quite complex). It functions as a vasodilator. If you go for a walk, for example, the blood vessels in your leg muscles must widen in order to increase blood flow, so your muscles get enough oxygen and sugar. Inside your brain some tiny vessels open and close all the time depending on which brain area needs momentarily more oxygen and sugar.

The hypothesis is, that the production of the proper amount of NO inside the body is impaired and blood vessels don't open any more, when the should. All these processes are very fast and are done in microseconds to seconds. An impairment of NO production would lead to a lot of symptoms. The muscles would not get enough energy and oxygen and would have to rely on an anaerobic metabolism. A lot of acid would build up inside the muscles. This could lead to pain and fatigue and muscle weakness. It could lead to brain fog, headaches etc. As well to an impaired and slow digestion (the guts need a lot of blood to transport all fats and sugars). And of course OI. In order to stand, the body must close the blood vessels inside the legs and open the blood vessels in the upper half of your body.

There are several studies, which show, that blood flow is severely impaired in CFS/ME patients and the vessels are highly inflexible.

 

[deleder2k]

@Jonathan Edwards, Do you have a theory why gamma globulin works for many patients? Unofficially a doctor named dr. Mette Johnsgaard at the Balder clinic in Oslo have 60 patients on 5ml Gammanorm weekly. All with ME defined by Canadian criterias. 50% of them are significantly better. I also heard dr. Mella speak in Stockholm, and he explained that they gave gamma globulin infusions to a patient that was so sick he/she couldn't get in to the hospital for Rituximab treatment. They gave the patient one single treatment with gamma globulin, and it helped a lot. If I am correct gamma globulin strengths the immune system, while Rituximab breaks it down.
Why is it that it could work? and is there any reasons that one shouldn't try it?

 

[melihtas]

I tried Vastarel (Trimetazidine) for a few months in the past and I didn't experience any improvements but reading this thread makes me want to try it again.

Link: Trimetazidine effects on restoring endothelial function

Effects of trimetazidine on endothelial nitric oxide synthase
NO has long been known as an endothelium-derived relaxing factor. It is a vasodilator that regulates vascular tone, and it has been used as a nitrate donor for angina pectoris and heart failure. Furthermore, its powerful antioxidant, anti-inflammatory and antithrombotic actions are key factors for vascular endothelial protection and the anti-atherogenic process [15]. Di Napoli et al [16] reported that, in an isolated rat heart model with an ischemia– reperfusion injury, administration of trimetazidine reduces myocardial dysfunction and prevents vascular endothelial damage by increasing endothelial nitric oxide synthase (eNOS) expression [16]. The authors suggested the importance of preserving the anatomical and functional integrity of endothelium in the circulation system, and demonstrated that trimetazidine has a significant cytoprotective effect on vascular endothelial cells, partly preventing eNOS reduction. The action of trimetazidine on eNOS appears to be causally linked to the beneficial effects that trimetazidine has on ascular endothelial integrity and function.

 

[melihtas]

Link: New Study Finds Sunlight Boosts Nitric Oxide Production

We suspect that the benefits to heart health of sunlight will outweigh the risk of skin cancer. The work we have done provides a mechanism that might account for this, and also explains why dietary vitamin D supplements alone will not be able to compensate for lack of sunlight.

This team of researchers found that your body's production of nitric oxide is separate from its production of vitamin D, so it follows that there are two completely separate sets of benefits. Until now, increased vitamin D had been thought to be the sole explanation for the sun's health benefits, but it appears from these latest findings that vitamin D is only one part of the story.4

Besides the benefits derived from increased vitamin D, the sun also provides relief from a wide variety of health problems from mechanisms separate from vitamin D. For a comprehensive overview, refer to our previous article on the sun’s benefits, but here are just a few:

• Improved mood and energy levels through the release of endorphins
• Better melatonin regulation and synchronization of your biorhythms
• Suppression of the symptoms of fibromyalgia and multiple sclerosis
• Treating skin diseases (including psoriasis, vitiligo, atopic dermatitis, and scleroderma) and antibiotic-resistant infections, such as MRSA
• Treating tuberculosis, neonatal jaundice, and possibly T cell lymphoma

 

[greeneagledown]

@greeneagledown

take a look at this

Thanks, @deleder2k, but I can't open the graph or make it bigger. Do you have a link to it or another way of displaying it?

 

[melihtas]

Thanks, @deleder2k, but I can't open the graph or make it bigger. Do you have a link to it or another way of displaying it?

 

[greeneagledown]

Thanks, @melihtas, and holy hell, that's impressive -- even for an open-label study. Even more impressive when you consider that a lot of healthy people with no diseases probably wouldn't score 100% in self-reported functioning.

This is too much hope and excitement, people. I'm not sure I can handle it.

 

[deleder2k]

This is from the first study published. Double-blind. I think this is it, Greeneagledown. At least for now. Why it only works on 2/3 remains a question though. I am looking forward to the when KTS-4-2012 is published. I think it will be this autumn. The participants of the study are the ones that were non responders of Rituximab. They are being treated with Enbrel, a TNF-α inhibitor.

 

[optimist]

Regarding the beginning of this thread - my testosterone results came back fine. I had normal levels.

 

[IreneF]

I responded to rituximab after about six months of treatment, but the effect lasted only 4-6 weeks. I felt like I would have needed more frequent infusions to maintain the effect. Perhaps this happens with some RA patients, too. I understand that fewer than half of them respond to ritux. Perhaps Dr. Edwards can gives us more info.

 

[deleder2k]

Around 2/3 respond rate from all studies conducted in Norway. I think that is what we can expect from the new study launching this fall.
@IreneF, that is why they're now giving one infusion, one more after 14 days, 3 months, 6 months, 9 months and one final after 15 months. I don't know how many you got. They think that this could make the effect last.

 

[optimist]

Just curious @IreneF, how strong was your response? Did you feel normal again, or just better?