Misreading a Flawed Study
By Geoffrey Kabat.
In April 2024, a colleague and I published an article discussing the first vaccine designed to prevent recurrent urinary tract infections in women. UTIs are one of the most common infections, affecting roughly fifty percent of all women, with nearly half going on to experience a recurrence within six-to-twelve months. Recurrent UTIs carry a significant toll in morbidity and mortality, accounting for up to six percent of all healthcare visits (roughly seven million visits) in the US and are estimated to cost up to US$1.6 billion annually. Finally, recurrent UTIs have a profound effect on women’s activity, health-related quality of life, and productivity.
Antibiotics are the only effective treatment for recurrent UTIs. Physicians prescribe them but are very concerned about the increasing problem of antibiotic resistance. For this reason, there is a great interest in “antibiotic-sparing modalities” to prevent UTIs, particularly vaccines.
Our article reviewed the results of a randomised clinical trial of the vaccine known as MV140. MV140 is a sublingual vaccine with four inactivated bacteria types that cause most UTIs. It has been available under the commercial name Uromune in many countries in the European Union, the UK, Australia, and New Zealand under special-access programs and on a compassionate use basis since 2010. The paper was published in the New England Journal of Medicine Evidence in 2022. The study included 240 women aged 18 to 75 from Spain and the UK with recurrent UTIs. Subjects received either the vaccine for three or six months, or placebo for six months. The primary endpoint was the number of UTIs in the nine months following three months of intervention.
The results appeared to be impressive. Among women in the placebo group, the median number of UTIs was 3.0, compared to zero in both groups receiving the vaccine, a difference that was statistically significant. Among women who received the placebo, 25 percent were free of UTIs compared with 56 percent and 58 percent of those who received the oral vaccine for three and six months, respectively. The authors concluded that “In this controlled trial … MV140 showed promising clinical efficacy in reducing recurrent UTI in women suffering from this condition.”
After reading the NEJM Evidence paper, I contacted one of the authors (Dr Curtis Nickel) to find out where the vaccine stood with regard to approval by the Canadian government. In March 2022, the Canadian healthcare company Red Leaf Medical had submitted an application to Health Canada for the licensing of MV140. Dr Nickel told me about difficulties the company encountered from the committee conducting the review. After waiting several additional months for some word of the outcome of the review, I decided to take a closer look at the paper.
First, I was surprised to find that there were slightly more premenopausal than postmenopausal women in the sample (111 vs. 104). This is strange since recurrent UTIs are more common in postmenopausal women. Second, in an earlier paper from the same group in 2017 testing the efficacy of MV140 in 75 women with recurrent UTIs (but with no placebo group), it is reported that 59 women (78 percent) given the vaccine reported no subsequent UTIs during the treatment and subsequent follow-up period. Of the 16 women who experienced a UTI recurrence, fourteen (87 percent) were postmenopausal.
These results are from two different studies. Nevertheless, if one considers the combined effects of the relatively small number of postmenopausal women in the clinical trial and the fact that the vaccine appeared to be less effective in postmenopausal women in the smaller study, this would suggest that the main driver of the result reported in the clinical trial was the apparent effect of the vaccine in premenopausal women.
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Was the pre/pos assigment random?