according to results from the phase 3 .
“The lack of clinical effect of B-cell depletion in this trial weakens the case for an important role of B lymphocytes in ME/CFS but does not exclude an immunologic basis,”, of the department of oncology and medical physics at Haukeland University Hospital in Bergen, Norway, and his colleagues wrote April 1 in .
The investigators noted that the basis for testing the effects of a B-cell–depleting intervention on clinical symptoms in patients with ME/CFS came from observations of its potential benefit in a subgroup of patients in previous studies. Dr. Fluge and his colleagues performed a three-patient case series in their own group that found benefit for patients who received rituximab for treatment of CFS (BMC Neurol. 2009 May 8;9:28.). A phase 2 trial of 30 patients with CFS also performed by his own group found improved fatigue scores in 66.7% of patients in the rituximab group, compared with placebo (PLOS One. 2011 Oct 19. ).
In the double-blinded RituxME trial, 151 patients with ME/CFS from four university hospitals and one general hospital in Norway were recruited and randomized to receive infusions of rituximab (n = 77) or placebo (n = 74). The patients were aged 18-65 years old and had the disease ranging from 2 years to 15 years. Patients reported and rated their ME/CFS symptoms at baseline as well as completed forms for the SF-36, Hospital Anxiety and Depression Scale, Fatigue Severity Scale, and modified DePaul Symptom Questionnaire out to 24 months. The rituximab group received two infusions at 500 mg/m2 across body surface area at 2 weeks apart. They then received 500-mg maintenance infusions at 3 months, 6 months, 9 months, and 12 months where they also self-reported changes in ME/CFS symptoms.
There were no significant differences between groups regarding fatigue score at any follow-up period, with an average between-group difference of 0.02 at 24 months (95% confidence interval, –0.27 to 0.31). The overall response rate was 26% with rituximab and 35% with placebo. Dr. Fluge and his colleagues also noted no significant differences regarding SF-36 scores, function level, and fatigue severity between groups.
Adverse event rates were higher in the rituximab group (63 patients; 82%) than in the placebo group (48 patients; 65%), and these were more often attributed to treatment for those taking rituximab (26 patients [34%]) than for placebo (12 patients [16%]). Adverse events requiring hospitalization also occurred more often among those taking rituximab (31 events in 20 patients [26%]) than for those who took placebo (16 events in 14 patients [19%]).
Some of the weaknesses of the trial included its use of self-referral and self-reported symptom scores, which might have been subject to recall bias. In commenting on the difference in outcome between the phase 3 trial and others, Dr. Fluge and his associates said the discrepancy could potentially be high expectations in the placebo group, unknown factors surrounding symptom variation in ME/CFS patients, and unknown patient selection effects.
“[T]he negative outcome of RituxME should spur research to assess patient subgroups and further elucidate disease mechanisms, of which recently disclosed impairment of energy metabolism may be important,” Dr. Fluge and his coauthors wrote.
The trial was funded by grants to the researchers from the Norwegian Research Council, the Norwegian Regional Health Trusts, the MEandYou Foundation, the Norwegian ME Association, and the legacy of Torstein Hereid.
SOURCE: Fluge Ø et al. Ann Intern Med. 2019 Apr 1.