SUMMARY: Could the positive results of the early Fluge & Mella 2011 blinded phase II rituximab trial and 2015 open label phase II study be due to inadvertently including some Giardia lamblia ME/CFS patients in the study cohort, from the 2004 Bergen Giardia lamblia outbreak?
The later Fluge & Mella negative 2019 phase III multi-center rituximab study would have had much fewer Giardia lamblia patients (because it was conducted in several other cities, not just Bergen).
On the assumption that rituximab works for Giardia lamblia ME/CFS, if there were Giardia lamblia patients in the two phase II studies, this might explain why these studies were positive, whereas the later phase III study was negative.
In 2004 in Bergen Norway, there was a major outbreak of giardiasis (Giardia lamblia infection) resulting from sewage contamination of the drinking water supply, which affected an estimated 2500 people (with 1300 actual laboratory-confirmed cases of giardiasis).
Bergen of course is the city where Oystein Fluge and Olav Mella conducted their phase II rituximab studies.
From March 2009 to March 2010, five years after the giardiasis outbreak, 253 patients who had been suffering chronic fatigue symptoms ever since their giardiasis were recruited to participate in a 2013 study at Haukeland University Hospital in Bergen. The study concluded that 41.5% of the participants had ME/CFS by the CDC Fukuda criteria.
So lots of patients with Giardia lamblia-triggered ME/CFS were attending the Haukeland University Hospital at the time Fluge & Mella were conducting their phase II rituximab trials at Haukeland. The Fluge & Mella 2011 phase II trial recruited ME/CFS patients referred to the Department of Neurology, Haukeland University Hospital, from June 2008 to June 2009.
So the question is, how many of these Giardia lamblia ME/CFS patients would have been included in the rituximab phase II trials? Giardia lamblia ME/CFS is a rare form of ME/CFS, so if lots of these patients got onto the phase II trials, it would have created an unusual patient cohort.
By contrast, the phase III multi-center rituximab study was conducted in various university hospitals in different cities in Norway (Bergen, Oslo, Notodden, Trondheim and Tromsø judging by the authors' affiliations in the study). So you would thus have had far fewer Giardia lamblia ME/CFS patients in the phase III study, because the giardiasis outbreak only occurred in Bergen.
Thus if rituximab were effective for Giardia lamblia ME/CFS, it might explain why the two phase II studies showed such positive results, but the phase III study had a negative result.
Just to remind you of Fluge & Mella's rituximab trial results:
2011 blinded phase II study on 30 ME/CFS patients given rituximab or placebo.
Response rate: 67% in the rituximab group, and 13% in the placebo group.
2015 open label phase II study on 29 ME/CFS patients all given rituximab. No placebo group.
Response rate: 64%.
2019 blinded phase III study on 151 ME/CFS patients given rituximab or placebo.
Response rate: 26% in the rituximab group, and 35% in the placebo group.