Yet Another Flawed "Placebo Controlled" Study in Crohn's Disease?

Dear Editor:

Accumulating data suggest that some variants of Crohn's disease (CD) may be consequent to a Mycobacterium avium subspecies paratuberculosis (MAP) infection. Opportunely, a prospective study (Kalfus, 2013) is addressing the therapeutic role of appropriate antimycobacterial antimicrobials in CD. Potential inflammatory bowel disease (IBD) benefits may include identification of a mycobacterial etiology, improvement on current therapies, and possibly prevention.

MAP is inhibited by agents that the scientific community categorizes as anti-inflammatory (Greenstein et al., 2007) and immune-modulators. (Krishnan et al., 2009) A much-cited 2007 “placebo controlled” trial of anti-MAP antibiotics concluded that there was “no significant role for MAP in the pathogenesis of CD” (Selby et al., 2007). Subsequent correspondence dismissed the possible corrupting influence of unanticipated “immune-modulator” anti-MAP inhibition as being “not consistent” with prevailing dogma. This was despite the editorial accompanying the 2007 study emphasizing significant improvement associated with concomitant use of “immune-modulators” (Selby et al., 2007).

Disconcertingly, the inclusion criteria in the ongoing study (Kalfus, 2013) are essentially identical to the prior “placebo”-controlled study (Selby et al., 2007). Both ignore MAP inhibition by “anti-inflammatory” (Greenstein et al., 2007) and “immune-modulators.” (Krishnan et al., 2009) The 2007 study (Selby et al., 2007) was designed before relevant MAP inhibition data (Greenstein et al., 2007; Krishnan et al., 2009) were published. The designers of the study now recruiting (Kalfus, 2013) should explain why they ignore unrefuted published data that render their “placebo-controlled” study as flawed as previously (Selby et al., 2007).

We suggest that calling the study now recruiting (Kalfus, 2013) “placebo-controlled” is unscientific (Greenstein et al., 2014). Multiple medications that inhibit infectious agents (Greenstein et al., 2014) are permitted in both the “placebo” as well as treated groups. (Greenstein et al., 2014). Previously, we have suggested that “add-on studies” is scientifically more accurate than “placebo-controlled” (Greenstein et al., 2014).

A consistently flawed study design may yet again be misinterpreted as showing no added efficacy of anti-MAP agents in CD. Consequently, the potential identification of the etiology of IBD as being due to the zoonosis of MAP may irrevocably be lost.