Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis

Ali, Ahmad H.; Damman, Jennifer; Shah, Shamita B.; Davies, Yinka; Hurwitz, Melissa; Stephen, Mariam; Lemos, Leta M.; Carey, Elizabeth J.; Lindor, Keith D.; Buness, Cynthia W.; Alrabadi, Leina; Berquist, William E.; Cox, Kenneth L.

doi:10.1080/00365521.2020.1787501

Cited by 36 publications

(30 citation statements)

References 45 publications

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“…In the prospective study by Ali et al, ( 1 ) 50% of children normalized GGT on OVT, an unremarkable finding when viewed alongside our data showing biochemical response in 53% of OVT, 49% of UDCA, and 52% of untreated groups. Ali et al’s study featured many patients with mild disease: an unusually high rate of small duct phenotype (42%, 4 times the rate seen in practice), minimal fibrosis in 40%, and some patients with normal pretreatment GGT.…”

supporting

confidence: 75%

Reply:

Deneau

2021

Hepatology

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is the objective reporting of virtually all prospective liver-disease and IBD research: hepatobiliary fibrosis measured using standardized histologic tools, cholangiography scored by radiologists blinded to treatment status, and IBD activity assessed by the Pediatric Ulcerative Colitis Activity Index, serum and fecal inflammatory markers, and endoscopy. Ali et al.'s findings may be hypothesis-generating for further research, but without untreated controls or objective outcomes, they do little to suggest efficacy of OVT. An individualized, informed consent process should include our data that the children most likely to "respond" to off-label OVT are those with low SCOPE indices, who are likely to do just as well without medication. Screening for vancomycinresistant enterococcus did not occur, leaving us with no data on this risk.In the end, one of the most important findings of our study was not the ineffectiveness of OVT, but rather the reasonable alternative to a conservative, "wait-and-see" approach. Our data are in opposition to the narrative that some treatment is always better than no treatment, particularly for the 60% of children with a low-risk SCOPE index. Future clinical trials will need to enroll patients who are untreated or willing to discontinue treatment. Use of off-label OVT on the basis of currently available uncontrolled data, case reports, and unpublished anecdotes has unclear benefits, unclear risks, and is likely to thin an already small pool of potential clinical trial participants.

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confidence: 75%

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Deneau

2021

Hepatology

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“…Results from two open‐labeled trials of OVT for PSC showed GGT normalization in 50% of children at 6 months, analogous to the results of any of the treatment strategies in this study. ( 29 ) This was true even though 3 times as many small duct PSC patients were included as in this analysis, a phenotype known to have favorable outcomes. ( 24,28 ) Two pilot randomized trials of OVT in adults suggested some potential benefits to biochemistry.…”

Section: Discussionmentioning

confidence: 99%

“…No rigorous surveillance guideline for vancomycin‐resistant enterococcus (VRE) is in place. The prospective pediatric trial of OVT for PSC did not routinely screen patients for VRE over a median of 4.5 years of treatment, ( 29 ) so how often VRE occurs in OV‐treated PSC is open for study. In a prospective clinical trial, >20% of adults treated with just 10 days of OVT for Clostridium difficile developed VRE.…”

Section: Discussionmentioning

confidence: 99%

Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis

et al. 2021

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Background and Aims Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. Approach and Results We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty‐four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention‐to‐treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma‐glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5‐year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. Conclusions We presented the largest‐ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end‐stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo‐controlled treatment trials are needed to identify effective treatments for pediatric PSC.

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“…Of note, the biochemical response to OVT was more favorable in the pediatric compared to the adult group. Besides, a significant proportion of patients showed improvements on histologic features and cholangiopathy[ 22 ]. Conversely, in a recent retrospective study on a large cohort of children with PSC the authors did not show improvement in outcomes of children treated with OVT or UDCA compared to those with “no treatment”[ 23 ], although several limitations were recorded in the study design[ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Use of oral vancomycin in children with autoimmune liver disease: A single centre experience

Giorgio¹,

Tulone²,

Nicastro³

et al. 2021

WJH

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BACKGROUND Previous reports showed some beneficial effect of oral vancomycin treatment (OVT) in children with primary sclerosing cholangitis; conversely, the experience in patients with other autoimmune liver diseases (AILD), including autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), is scant. AIM To assess the response to immunosuppressive treatment (IS) and to OVT in children diagnosed with AILD. METHODS Retrospective study of children diagnosed with AIH (normal biliary tree at cholangiography) and ASC (abnormal biliary tree at cholangiography) in the last 10 years. All underwent standard immunosuppressive therapy (IS), but non-responders received also OVT. Biochemical remission [normal aspartate aminotransferase (AST)] and immunological remission (normal IgG and negative autoantibodies) rates and Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index were assessed and compared during the follow up. RESULTS 75 children were included [69% female, median age 10.5 years (5.6-13.4 years), AIH = 54, ASC= 21]. Sixty-three patients (84%, AIH = 52, ASC = 11) were treated with standard IS and 61 achieved biochemical remission, whereas 12 not responding to IS [16%, F = 75%, median age 13.5 years, (12.2-15.7), 10 with ASC] required OVT and 8 achieved biochemical remission. Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81% (61/75) to 92% (69/75). Median values of AST, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) decreased significantly after OVT start ( P < 0.05). Complete normalization of livers enzymes (AST, ALT and GGT) was observed in 6/12 patients (50%). Decrease in SCOPE index score was reported in 5/12 patients (42%). At last follow up (median of 4.4 years, range 0.6-13.8 years) all 75 patients are alive, 6 (8%, 1 with ASC) successfully discontinued medications, 1 (with ASC) required liver transplantation. CONCLUSION Children with AIH and ASC respond well to IS treatment. OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS. These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.

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Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis

Cited by 36 publications

References 45 publications

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Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis

Use of oral vancomycin in children with autoimmune liver disease: A single centre experience

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