Open Norway: Plasma cell aimed treatment with daratumumab in ME/CFS - Haukeland University Hospital

The ME/CFS research team at Haukeland University Hospital in Bergen, Norway (Fluge, Mella, Rekeland, Sørland etc) is recruiting 66 participants for a new placebo-controlled trial on Daratumumab as a potential treatment for ME/CFS.

The duration for participants is 72 weeks. The participants will fill out surveys on a regular basis, use a Fitbit-watch to monitor physical activity and heart rhythm, receive Daratumumab (or placebo) as an injection three times with two weeks apart. Then a new treatment after 24 and 26 weeks. Blood work is done before every treatment and there will be follow up on a regular basis on phone. There will also be two consultations with a doctor which includes blood work and physical examination.

Information in Norwegian for those who want to apply:
https://www.helse-bergen.no/klinisk...-rettet-behandling-med-daratumumab-ved-mecfs/

 

The Norwegian ME Association has already put aside 4 million NOK in order to support this study and is now starting a campaign to raise more money in order to ensure its funding.

https://www.me-foreningen.no/me-fondet-gir-fire-millioner-til-daratumumab-studie-pa-haukeland/

 

≈
350k Eur
290k GBP
390k USD

 

Very exciting to finally be able to investigate if long lived plasma cells are involved. I remember discussing this with @Jonathan Edwards at the old forum. What do you think?

 

Some (translated) information from the above website that seems valuable:

• 2/3 drug, 1/3 placebo
• Placebo appears to be saline (so not an active placebo that mimics Daratumab or offers full unblinded control, which might be hard to do with Daratumab and saline is typically used in Daratumab trials, but more to control for some other effects, regression to the mean, Hawthorne effect)
• To participate in the study, you must be diagnosed with ME/CFS according to the 2003 Canadian criteria, with illness duration of at least two years.
• The severity of the illness must be from moderate (essentially housebound) to severe (essentially bedridden). In addition, the ME/CFS illness must have started at a defined time, typically after an infection.
  
• Potential candidates complete a set of questionnaires online, and then undergo a medical examination with clinical examination, interview and blood tests to rule out other diseases or weakened immune systems. If you are included in the study, physical tests will also be performed before and at the end of the study to record any changes. We adapt the physical tests as best we can to the individual participant's activity level and tolerance. Both initial and final examinations in the study will be conducted at Haukeland University Hospital.
  
• Treatment starts after 12 weeks, with the first 12 weeks serving as baseline reference.
• If trial results will be positive the following trial will have a cross-over setup.

 

I think it is courageous and justified. Whether or not it will tell us something important I do not know but if anyone is going to do this, these are the right people.

 

As I understand it crossover means placebo and drug groups switch round after the initial phase right? So are they saying this will be the case for phase 3 or are they using it in a different sense here?

 

This sounds more like an open follow-up with drug for the control group rather than a formal switch round.

Blinding is going to be difficult if patients need IgG monitoring and replacement with infection.

 

Unfortunately, only patients residing in Norway can participate.

 

Rituximab kills cells carrying CD20, which is mostly B cells rather than their daughter plasma cells. B cells and new supply of B cells are mostly removed for about 5 months with a standard dosing. Short lived plasma cells presumably die off with the lack of supply of new ones from B cells but long lived plasma cells will not.

Daratumumab kills cells carrying CD38, which includes quite a lot of lymphoid cells but is particularly expressed on plasma cells. Daratumumab will kill a proportion of plasma cells already making antibody, including long lived cells.

If the problem in ME/CFS comes from antibody populations set up some time before, following an infection and produced by long lived plasma cells daratumumab would have logic to it.

 

Also this criteria which they brought up in their talks.

Baseline NK cell count must be ≥ 125 x109/L

 

It looks like serum IGG starts to come back after about a year. Does this mean your vulnerability to infection declines at this point? Does a person need to be re-vaccinated at this point?

{Noted that in this trial they will inject Daratumumab again at weeks 24 and 26, so that the time spent immunocompromised will be increased}

 

These are still open questions I think. We had very little trouble with low IgG with rituximab because we were careful. In France physicians used it without being careful and there were infection deaths. A lot of protection against viral infections going around is T cell based. It takes too long to make antibody to keep you alive during a new infection anyway. But there is likely to be some increased risk with IgG being low.

 

From the Norwegian MEA.
https://www.me-foreningen.no/me-fondet-gir-fire-millioner-til-daratumumab-studie-pa-haukeland/The ME Fund provides four million for a large clinical trial on Daratumumab in Haukeland - The Norwegian ME Association

 

Fluge also said in an interview that they have not been successful in securing grants from others.

 

This just goes to show how deep the predudice against ME runs in pharma and funding. You couldn't ask for more methodical and dedicated people to run your trials.

The pharma part makes the least sense because as Mella says, if a phase 3 showed the same results as the pilot and the cyclo studies that would be millions of potential responders...

 

Interview in Norwegian:

https://www.youtube.com/watch?v=lVGWLCdXhsE

Øystein Fluge forteller om den nye studien med Daratumumab til ME-pasienter, på Haukeland sykehus - YouTube

An interesting mention towards the end is that they have done a study where they followed patients without doing anything to them, in order to get a clearer picture of how their symptoms fluctuate over time.

He says that they decided against including mild patients because they fluctuate too much. I think this is notable if you consider that most other studies only include mild/moderate patients.

He also says that the criteria for being classified as responders are a lot stricter this time around.

He goes quite far in saying that he believes this treatment can have a positive effect, but he also puts a lot of emphasis on how there are no guarantees and that we can’t say anything before we’ve actually got the data.

 

The trial will cost approximately 26 million NOK (2568066 USD, 2200842 EUR, 1870892 GBP) in total, so there's still a long way to go, but 4 million NOK is a start.