A "Screen and Treat" Helicobacter Pylori Eradication Trial in Adolescents in Three Regions of Chile

Sponsor

Miguel O'Ryan Gallardo (Other)

Overall Status

Recruiting

CT.gov ID

NCT05926804

Collaborator

Fondo Nacional de Desarrollo Científico y Tecnológico, Chile (Other)

500

Enrollment

Locations

Arms

43.9

Anticipated Duration (Months)

166.7

Patients Per Site

3.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 1000 asymptomatic adolescents 14-18 years of age from 3 cities of Chile (Colina, Temuco and Coyhaique), to find a total of 200-250 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".

Condition or Disease	Intervention/Treatment	Phase
Helicobacter Pylori Infection	Drug: Lansoprazole Drug: Amoxicillin Drug: Clarithromycin Drug: Metronidazole	N/A

Detailed Description

Background: Helicobacter pylori (H. pylori) infection is the main cause of gastric cancer (GC), and long-term process occurs from premalignant lesions to carcinoma. H. pylori eradication during early stages of disease in young adults ("screen and treat") significantly impacts GC favoring survival, disease reversal and molecular changes. Effects of eradication therapy in affecting gut microbiome diversity and composition, and increasing antibiotic resistance rates in commensal bacteria, appear to be transient in most studies. The investigators have shown that infection is acquired mainly during the first 5 years of life, most infected children remain persistently infected with low rates of spontaneous eradication and persistently infected children have more abdominal complaints and higher levels of pepsinogen (PG) II (marker of gastric damage). A pilot eradication trial in persistently infected school-aged children showed that with sequential triple therapy, eradication was achieved in 96.8% of children, and treated children had a decrease in PG I and II levels compared to non-treated. The Investigators propose a "screen and treat" strategy aimed at a transition age between childhood and adulthood, in areas with intermediate-high gastric cancer prevalence, to assess efficacy of eradication, its clinical and molecular benefits and potential microbial side effects. Aims: The primary aim will be to determine the effectiveness of H. pylori eradication therapy in 14-18 years old adolescents in three regions with nearly 20-25% persistence rates, and determine the effect of eradication on clinical and serum biomarkers of gastric disease/damage. The secondary aims will be to determine the effects of H. pylori eradication therapy on antimicrobial resistance of potentially pathogenic enteric bacteria, and on gut microbiome composition. Exploratory aims: To determine the presence of clarithromycin resistance genes in H. pylori by stool analysis of children not achieving eradication, and determine the effects of reinfection on clinical findings indicative of gastric disease, and biomarkers indicative of "gastric damage", gut microbiota composition and antimicrobial resistance of H. pylori and other potentially pathogenic bacteria. Methods: The Investigators will invite, through contact with the health and educational authorities of Colina, Temuco and Coyhaique, 14-18 year old students until we reach 1000 adolescents enrolled. H. pylori screening test (Urea Breath Test; UBT) will be offered, and adolescents with a positive test will undergo two additional tests, separated by 30 days, in order to confirm infection persistence (at least two positive tests). It is expected that 20-25% of adolescents screened to be positive for H. pylori, of which over 90% will be persistently infected. Subjects will then be randomized 2:1 to receive either an antimicrobial course targeting H. pylori eradication (7 days of lansoprazole and amoxicillin followed by 7 days of lansoprazole and clarithromycin plus metronidazole) or no treatment. Participants will be followed-up with UBT (1 month post treatment, and then every 6 months for the remaining surveillance period), gastroenterological evaluation (2 weeks pre treatment, 1 month, 3 months, 9 months and 18 months post treatment), blood samples and stool samples (2 weeks pre-treatment, 1 month and 6 months post treatment). A subset of 60 non-infected students from each site will be followed-up in matched times. Serum gastric damage biomarkers will be assessed using GastroPanel® (PGI, PGII, Gastrin) and ELISA commercial kits (VCAM-1, CXCL13). Escherichia coli and Enterococcus spp will be cultured from stools samples, and resistance to 6 antimicrobials will be assessed by disk diffusion method.

pylori clarithromycin resistance gene will be amplified from stools using nested-qPCR. Composition of gut microbiome will be characterized by amplification and sequencing the 16SrRNA gene from stools, ant then bioinformatics analysis. Expected results: The prevalence of persistent H. pylori infection will be around 20-25% in adolescents from Colina, Coyhaique and Temuco. Eradication will be successful in >90% of persistently infected students, and reinfection rates will not surpass 15% in a 2-3 year period. Eradication will be significantly associated with a decrease in clinical findings indicative of gastric disease, and a decrease in biomarker levels indicative of "gastric damage". Treatment will have a transitory effect on increasing antimicrobial resistance rates of potentially pathogen enteric bacteria (Escherichia coli, Enterococcus spp.). Treatment will have a transitory effect on disrupting gut microbiota composition at phylum, class, order, family and genus levels, which will be restored to levels comparable to non-infected healthy teenagers at the end of follow-up. In those adolescents for whom eradication therapy fails, clarithromycin resistance will be more prevalent in pretreatment samples compared to those eradicating H. pylori; in reinfected children, treatment will have a transitory effect on increasing detection rates of H. pylori clarithromycin resistance genes.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Screening phase: We will invite 14-18 year old students from three cities until we reach 1000 adolescents. After informed consent, those who meet inclusion criteria and don't have exclusion criteria will be offered an H. pylori screening test (Urea Breath Test; UBT or stool antigen test; SAT). Subjects negative for the screening test will be discharged from the study, except for a subset to be followed as a non-infected control group. Subjects with a positive test will undergo two additional tests separated by 30 days, in order to confirm infection persistence, defined by at least two positive tests. We expect 20-25% of subjects screened to be positive Intervention phase: Individuals with persistent H. pylori infection will have a gastroenterological evaluation during the month prior to treatment, and will then be randomized 2:1 to receive either an antimicrobial course targeting H. pylori eradication or no treatment. Non-infected controls will be followed-up in matched times.Screening phase: We will invite 14-18 year old students from three cities until we reach 1000 adolescents. After informed consent, those who meet inclusion criteria and don't have exclusion criteria will be offered an H. pylori screening test (Urea Breath Test; UBT or stool antigen test; SAT). Subjects negative for the screening test will be discharged from the study, except for a subset to be followed as a non-infected control group. Subjects with a positive test will undergo two additional tests separated by 30 days, in order to confirm infection persistence, defined by at least two positive tests. We expect 20-25% of subjects screened to be positive Intervention phase: Individuals with persistent H. pylori infection will have a gastroenterological evaluation during the month prior to treatment, and will then be randomized 2:1 to receive either an antimicrobial course targeting H. pylori eradication or no treatment. Non-infected controls will be followed-up in matched times.

Masking:

Single (Outcomes Assessor)

Masking Description:

Blinded Gastroenterologist or trained physician who performs the surveillance after eradication treatment. No other parties will be masked in the clinical trial.

Primary Purpose:

Treatment

Official Title:

A "Screen and Treat" Helicobacter Pylori Eradication Trial in 14-18 Years Old Adolescents Residing in Three Regions of Chile: Effectiveness and Microbiological-host Implications

Actual Study Start Date :

Aug 2, 2022

Anticipated Primary Completion Date :

Apr 30, 2024

Anticipated Study Completion Date :

Mar 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cases 150-160 children with H. pylori-persistent infection, who will receive eradication therapy	Drug: Lansoprazole 14 days of Lansoprazole (30 mg BID) (days 1-14) Drug: Amoxicillin 7 days of Amoxicillin (1000 mg BID) (days 1-7) Drug: Clarithromycin 7 days of Clarithromycin (500 mg BID) (days 8-14) Drug: Metronidazole 7 days of Metronidazole (500 mg BID) (days 8-14)
No Intervention: Controls 75-80 children with H. pylori-persistent infection, who will not receive eradication therapy
No Intervention: Non infected Controls 60 adolescents with no H. pylori infection, they will not receive eradication therapy

Arm

Intervention/Treatment

Experimental: Cases

150-160 children with H. pylori-persistent infection, who will receive eradication therapy

Drug: Lansoprazole

14 days of Lansoprazole (30 mg BID) (days 1-14)

Drug: Amoxicillin

7 days of Amoxicillin (1000 mg BID) (days 1-7)

Drug: Clarithromycin

7 days of Clarithromycin (500 mg BID) (days 8-14)

Drug: Metronidazole

7 days of Metronidazole (500 mg BID) (days 8-14)

No Intervention: Controls

75-80 children with H. pylori-persistent infection, who will not receive eradication therapy

No Intervention: Non infected Controls

60 adolescents with no H. pylori infection, they will not receive eradication therapy

Outcome Measures

Primary Outcome Measures

Percentage of persistently-infected teenagers which change UBT status from positive to negative 1 month post-treatment, as compared to non-treated subjects. [a. Baseline: 2 or 3 samples obtained pre-treatment (separated by 30 days) to detect persistently infected children b. One month post-treatment.]
UBT samples will be obtained pre-treatment and 1 month post-treatment
Change in the percentage of persistently-infected teenagers of the treatment-arm which have "gastric disease" according to gastroenterologist examination from baseline (pre-treatment) to 2-4 months, as compared to non-treated subjects. [a. Baseline evaluation during the month prior to treatment. b. 2-4 months post treatment]
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).
Change in blood levels of biomarkers indicative of gastric damage in treated as compared to non-treated subjects after 6 month follow up. [a. Baseline: Within 2 weeks before initiation of eradication treatment and at similar time-frame in non-treated age matched controls (pre-sample) b. 1 month after treatment c. 6 months post treatment]
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.

Secondary Outcome Measures

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. [a. Baseline: Within one month before treatment b. 1 month post treatment c. 6-12 months post treatment (and at similar time-frame in non-treated age matched controls)]]
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. [a. Baseline: Within one month before treatment b. 1 month post treatment c. 6-12 months post treatment (and at similar time-frame in non-treated age matched controls)]]
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
Effect of treatment on frequency of clarithromycin resistance comparing those subject who would not eradicate with non-treated individuals [a. Baseline: Within 1 month before eradication b.Within 3 months after the positive UBT sample indicating non-eradication or reinfection.]
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 or SAT sample indicating non-eradication or reinfection in conjunction with testing of a similar number of non-treated UBT or SAT 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

14 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

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)

Exclusion Criteria:

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
Antimicrobial course received during the previous month (at least 3 days of treatment at appropriate dosing, children meeting this criteria can be included at a later stage)
Pregnancy
Use of immunosuppressive or biologic drugs
Known allergy to antimicrobials included in eradication scheme
Children deemed "not healthy" after review of the questionnaire by study physician