Gastric cancer remains a global health problem, and Chile has one of the highest GC mortality rates in the region. Helicobacter pylori (H. pylori) infection is ubiquitous in Chilean adults, and it constitutes the main cause of GC worldwide. A long-term process occurs from premalignant lesions to carcinoma. H. pylori eradication during early stages of disease significantly impacts outcomes, favoring survival, disease reversal and molecular changes, which supports a "screen and treat" strategy in asymptomatic populations in areas with intermediate-to-high GC prevalence. The Investigators' previous research has shown that H. pylori infection is acquired in early childhood with low rates of spontaneous eradication. A pilot treatment study in a subset of school-aged asymptomatic children showed a high rate of successful eradication (\>95%), good tolerance, and was associated with a decrease in serum biomarkers of gastric damage (pepsinogen I and II). Based on the results of these studies, the Investigators propose to advance towards the next stage of this research process: a "screen and treat" strategy. The current trial starts with a Screening phase testing up to 1000 asymptomatic adolescents 14-18 years of age from 3 cities of Chile (Colina, Temuco and Coyhaique), to find a total of 210 persistently-infected participants. Persistently-infected adolescents will be included in a Second phase of this trial: A randomized, case-control, non-blinded study to either receive antimicrobial treatment targeting H. pylori eradication (cases) or no treatment (controls). A subset of 60 non-infected adolescents will be followed-up in matched times. This aims to provide evidence on the effect of treatment on clinical outcomes and serum biomarkers related to gastric damage, as well as composition and antimicrobial resistance of gut microbiota. The Investigators expect that eradication therapy will be successful in \>90% of persistently infected adolescents, with reinfection rates not surpassing 15% in a 2-3 year period, and to be associated with a decrease in clinical findings indicative of gastric disease, and a decrease in serum biomarker indicative of "gastric damage".
Healthy teenagers 14-18 years of age from Colina, Temuco or Coyhaique
At least one responsible adult family member accessible for phone contact.
Persistent H. pylori infection determined by at least 2 positive UBT tests in a 3 months period (except for Non-infected Controls)
Teenagers not consenting to treatment will be invited to continue as non-treated controls.
Known allergy to any of the antimicrobials used in the trial protocol (except for Non-infected Controls)
Signs/symptoms compatible with organic abdominal pain according to Rome IV criteria: persistent right upper or right lower quadrant pain, dysphagia, odynophagia, persistent vomiting, gastrointestinal blood loss, involuntary weight loss, deceleration of linear growth, delayed puberty.
Prior eradication therapy
Parallel
Lansoprazole
Drug14 days of Lansoprazole (30 mg BID) (days 1-14)
Amoxicillin
Drug7 days of Amoxicillin (1000 mg BID) (days 1-7)
Clarithromycin
Drug7 days of Clarithromycin (500 mg BID) (days 8-14)
Metronidazole
Drug7 days of Metronidazole (500 mg BID) (days 8-14)
Percentage of persistently-infected teenagers which change UBT status from positive to negative 1 month post-treatment, as compared to non-treated subjects.
UBT samples will be obtained pre-treatment and 1 month post-treatment.
Change in the percentage of persistently-infected adolescents which have "gastric disease" according to gastroenterologist examination from baseline (pre-treatment) to 2-4 months post successful eradication therapy, as compared to non-treated subjects
Clinical evaluation by gastroenterologist or trained physician, blind to the treatment arm of the subject, for specific GI signs/symptoms, will be performed at baseline (during the month prior to treatment) and posttreatment (2-4 months post treatment). Successful eradication: Negative UBT sample 30 days after treatment
Change in blood levels of biomarkers indicative of gastric damage in adolescents with successful eradication after treatment, as compared to non-treated subjects after 6 month follow up.
Blood samples for Pepsinogen (PG) I, PGII, gastrin and other potential biomarkers of "gastric damage. PGI/PGII/Gastrin-17: will be assessed in serum using GastroPanel® (Biohit Oyj, Helsinki, Finland). Two additional biomarkers of GC will be assessed by ELISA-commercial kits: VCAM-1 and CXCL13. Samples will be collected at baseline, 1 month and 6 months post treatment.
Change in faecal Escherichia coli and Enterococcus antimicrobial resistance rates in treated subjects from baseline to 1 month and 6-12 months post treatment, as compared to non-treated subjects.
Phenotypic antimicrobial susceptibility analysis of Escherichia coli and Enterococcus will be performed from stool samples obtained in both Cases and Controls by Kirby Bauer disc diffusion method. According to patterns of AMR of each bacteria, and the antimicrobials used in this trials, E. coli will be tested against clarithromycin, ampicillin, ampicillin-sulbactam, cefazolin, ceftazidime, levofloxacin, and gentamicin; and Enterococcus will be tested against clarithromycin, ampicillin, ampicillin-sulbactam, penicillin, vancomycin and quinopristin/dalfopristin.
Change in gut microbiome alpha-diversity index in treated subjects from baseline to 1 month and 6-12 months post-treatment, as compared to to non-treated subjects.
For microbiome analysis 30 stool samples from each group (Cases and controls) will be obtained pre and post treatment. Changes in gut microbiota composition in stool samples will be analyzed by sequencing of the 16S rRNA V3 to V4 hypervariable region using Illumina
Prevalence of H.pylori persistent infection in adolescents in Colina, Temuco and Aysén
Persistent infection will be defined by at least 2 positive UBT tests in a 3 month period during the screening phase. Two initial UBT tests will be performed separated by 1 month; a third UBT test will be obtained If there is a discordance in results of the first two tests.
Effect of treatment on frequency of clarithromycin resistance comparing those subject who would not eradicate with non-treated individuals
Stool evaluation for presence of Clarithromycin resistance genes will be performed in stool samples obtained before eradication (30 in each group), and after the positive UBT sample indicating non-eradication in conjunction with testing of a similar number of non-treated UBT-positive subjects (20 in each group, including 10 treated and non-eradicated subjects). From DNA isolated from stools, qPCR for ureC will be performed to confirm H. pylori infection, and then qPCR to 23SrRNA gene mutations by Taqman probes will be performed.
Overall reinfection rates in adolescents with successful eradication after treatment
UBT test performed 1 month after the last day of treatment to confirm eradication, and then 6 months after treatment and subsequently every 6 months to evaluate reinfection up to 24 months post treatment. Reinfection: adolescents in whom H. pylori is successfully eradicated post-treatment, but who then become persistently positive during the remainder of the follow-up period
Change in the percentage of adolescents which have "gastric disease" according to gastroenterologist examination from post eradication to post reinfection.
Clinical evaluations by a gastroenterologist or trained physician, blinded to the subject's treatment arm, will be conducted after successful eradication (2-4 months post-treatment), and subsequently at 9-12 months and 18-24 months post-treatment to assess specific GI signs and symptoms and their changes in relation to reinfection during this follow-up period.
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Miguel O'Ryan Gallardo
Lead sponsor
University of Chile
Sponsor institution
Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
Collaborator
