This is a disappointing. Vanco phase 3 trial failed.
I’m very curious of what type of Vanco they used. PSCers know that you need ANI brand or to open the capsules. There is even a case report study about this. So I would be curious to look at the variable findings in the literature and examine exactly what manufacturer or instructions for consumption were provided. To me this is an important detail and it’s so disappointing to think this might meaningfully impact clinical care for those with PSC when maybe they just weren’t getting the medicine in the right way! My husbands scores were all completely normalized on oral vanco. He has had no disease progression and really no flairs since starting it over 3 years ago. It has changed our lives and I really hope it continues to be supported as a treatment option.
Agreed to this trial not being representative of how PSC patients take vancomycin.
There’s a caution section already stated in the article about this, pasting below for visibility.
I read the source paper, Oral Vancomycin Is Not Associated With Meaningful Changes in Liver-Related End Points Among Adults With Primary Sclerosing Cholangitis: A Randomized, Placebo-Controlled Trial, this review talks about. The PDF explicitly says “Unauthorized reproduction of this article is prohibited,” which I think is unethical considering the title itself may affect the course of care for many PSC patients yet PSC patients don’t have access to it.
A few points I’d like to re-iterate and add, some of which were mentioned in my vitamin D post and responses:
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Only 82 patients were enrolled in the trial. Generally, phase 3 trials (such as the other ones for PSC) have around 300 patients, if not more. 47 out of 82 withdrew from the study. That’s a total of 35 patients who completed the study, of which 15 were on oral vancomycin. That cannot really be considered a phase 3 trial.
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Vancomycin was taken orally 125 mg 4 times a day (500 mg / day) for six months, then 250 mg 4 times a day (1000 mg / day) for six months, then 375 mg 4 times a day (1500 mg / day) for six months. Most PSC patients who are adults take 1500 mg / day right off the bat rather than ramping up. It’s known by the practitioners that taking lower doses of vancomycin can lead to the silent progression that they mention in the article where the enzymes reduce but the disease continues to progress.
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The patients took Azurity Pharmaceuticals, not ANI. I also think they took a liquid solution because the study notes discoloration of teeth and tongue as a side effect which is unlikely to happen with pill-based oral vancomycin. I don’t know if this makes a difference, or what’s special about pill form and ANI, and this is a mystery that bugs me, so someone with more experience should comment here.
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Most of the patients in the study appear to be at later stages of disease and older. Oral vancomycin has been shown to be more effective in younger populations at earlier stages of disease, so this may not be representative. The paper Identifying a therapeutic window of opportunity for people living with primary sclerosing cholangitis: Embryology and the overlap of inflammatory bowel disease with immune-mediated liver injury goes into more detail about the age and stage of disease where vancomycin would be most appropriate.
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Here’s a paper, Oral Vancomycin Is an Effective Therapy in Adult Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis, that is not placebo controlled but shows improvement in PSC-IBD patients with vancomycin (73 patients) with both monitoring of liver markers and endoscopy. There’s also ample case reports on PubMed.
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There are more trials being conducted in Europe. We’d have to wait for those studies to come back before making conclusions and consider the evidence as a whole.
Caution
The study should not be interpreted as proof that oral vancomycin has no effect in PSC. The trial was terminated early because recruitment was slow. Eighty-two patients were randomized instead of the planned 94. The authors estimate that the study had about 80% power to detect an absolute difference in SAP normalization of approximately 19% or greater. So, a relatively small treatment effect cannot be excluded.Attrition is another concern. Patients who withdrew early were less likely to describe their baseline health as excellent or very good and reported more impairment in several PBC-40 domains. This is important because patients with more symptoms or poorer quality of life may be harder to retain in a long clinical trial. At the same time, several findings make a major false-negative result less likely. Withdrawal rates and baseline prognostic characteristics were generally similar between treatment groups; patients who withdrew did not appear to have a hidden biochemical response; and the ITT, modified ITT, and per-protocol analyses were overall consistent.
There are also some interesting subgroup findings. Greater SAP reductions were reported in patients without IBD, those without liver stiffness in the cirrhotic range, and those not taking UDCA. These analyses are small and should be considered hypothesis-generating rather than evidence for selecting patients for treatment.
A second limitation is the primary endpoint itself. Although lower or improving SAP is associated with better prognosis in PSC, spontaneous fluctuations and normalization occur, and it remains unproven that a treatment-induced decline in alkaline phosphatase predicts improvement in long-term clinical outcomes.11 No surrogate biomarker has been sufficiently validated to replace clinical endpoints such as hepatic decompensation, hepatobiliary cancer, transplantation, or death in PSC trials. The study was not designed or powered to determine whether oral vancomycin affects these longer-term clinical outcomes.
Chronic antimicrobial exposure is an additional consideration: although no vancomycin-resistant enterococcal infections were observed, participants were not systematically screened for asymptomatic colonization with resistant organisms, limiting conclusions about the broader antimicrobial-resistance risk of prolonged therapy.
Milly,
Thank you for following up on the results of this study on Vancomycin. The effectiveness in adult patients has been debated for years. I didn’t have the opportunity to take Vanco prior to my transplant but have seen the effects of it post-transplant. I do believe it helps greatly in keeping inflammation of the bile ducts under control, and for me that has been so needed. I’m on 250 mg 4 times a day and a low dose Cipro once daily, I’m staying out of the hospital from bile duct infection due to GI tract reflux into the Roux-en-Y. Thanks again for sharing this insight.
Mark Wilson
PSC 2011 / Transplant 2015