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

• ClinicalTrials.gov Identifier: NCT05926804
• Recruitment Status: Recruiting
• First Posted: July 3, 2023
• Last Update Posted: January 5, 2024
• Sponsor: Miguel O'Ryan Gallardo
• Collaborator: Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
• Information provided by (Responsible Party): Miguel O'Ryan Gallardo, University of Chile

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	Not Applicable

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. To those subjects with persistent infection who do not receive treatment, the same eradication regimen will be offered after they have completed the initial 6-month follow-up with their blood and stool samples taken.

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. H. 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 (Clinical Trial)
• Estimated Enrollment: 500 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Screening phase: 14-18-year-old students (up to 1000) from three cities will be invited. After obtaining informed consent, eligible participants without exclusion criteria will undergo an H. pylori screening test (Urea Breath Test; UBT or stool antigen test; SAT). Those negative will exit, except for a subset to be followed as a non-infected controls. Subjects with a positive test will undergo two confirmatory tests 30 days apart to confirm infection persistence. Approximately 20-25% are expected to be positive.

Intervention phase: those with persistent H. pylori infection will undergo gastroenterological evaluation 1 month before randomization (2:1) to receive antimicrobial treatment or no treatment. Non-infected controls will be followed at matched intervals. If untreated, subjects with persistent infection will be offered the eradication regimen after completing the initial 6-month follow-up with blood and stool samples taken.

• 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: August 2, 2022
• Estimated Primary Completion Date: April 30, 2024
• Estimated Study Completion Date: March 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

Outcome Measures

Primary Outcome Measures :

1. Percentage of persistently-infected teenagers which change UBT status from positive to negative 1 month post-treatment, as compared to non-treated subjects. [ Time Frame: 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
2. 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. [ Time Frame: 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).
3. Change in blood levels of biomarkers indicative of gastric damage in treated as compared to non-treated subjects after 6 month follow up. [ Time Frame: 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 :

1. 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. [ Time Frame: 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.
2. 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. [ Time Frame: 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
3. Effect of treatment on frequency of clarithromycin resistance comparing those subject who would not eradicate with non-treated individuals [ Time Frame: 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

• Ages Eligible for Study: 14 Years to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Healthy teenagers 14-18 years of age from Colina, Temuco or Coyhaique
2. At least one responsible adult family member accessible for phone contact.
3. Persistent H. pylori infection determined by at least 2 positive UBT tests in a 3 months period (except for Non-infected Controls)

Exclusion Criteria:

1. Teenagers not consenting to treatment will be invited to continue as non-treated controls.
2. Known allergy to any of the antimicrobials used in the trial protocol (except for Non-infected Controls)
3. 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.
4. Prior eradication therapy
5. 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)
6. Pregnancy
7. Use of immunosuppressive or biologic drugs
8. Known allergy to antimicrobials included in eradication scheme
9. Children deemed "not healthy" after review of the questionnaire by study physician

Contacts and Locations

Contacts

Contact: Yalda Lucero, MD, PhD; +56997330860; ylucero@uchile.cl

Contact: Sergio George, MD, PhD; +56225756103; sgeorge@ug.uchile.cl

Locations

Chile

Universidad de Aysén; Recruiting

Coyhaique, Chile

Contact: Beatriz Zabala, PhD +56996503803 beatriz.zabala@uaysen.cl

Universidad de Chile; Recruiting

Santiago, Chile

Contact: Sergio George, MD, PhD +56225756103 sgeorge@ug.uchile.cl

Universidad de la Frontera; Recruiting

Temuco, Chile

Contact: Lilian Fernández, MD +56984282646 liliufro@gmail.com

Sponsors and Collaborators

Miguel O'Ryan Gallardo

Fondo Nacional de Desarrollo Científico y Tecnológico, Chile

Investigators

• Principal Investigator: Miguel O'Ryan, MD; University of Chile

More Information

Publications:

O'Ryan ML, Lucero Y, Rabello M, Mamani N, Salinas AM, Pena A, Torres-Torreti JP, Mejias A, Ramilo O, Suarez N, Reynolds HE, Orellana A, Lagomarcino AJ. Persistent and transient Helicobacter pylori infections in early childhood. Clin Infect Dis. 2015 Jul 15;61(2):211-8. doi: 10.1093/cid/civ256. Epub 2015 Apr 2.

O'Ryan ML, Rabello M, Cortes H, Lucero Y, Pena A, Torres JP. Dynamics of Helicobacter pylori detection in stools during the first 5 years of life in Chile, a rapidly developing country. Pediatr Infect Dis J. 2013 Feb;32(2):99-103. doi: 10.1097/INF.0b013e318278b929.

Lucero Y, Lagomarcino AJ, Torres JP, Roessler P, Mamani N, George S, Huerta N, Gonzalez M, O'Ryan M. Helicobacter pylori, clinical, laboratory, and noninvasive biomarkers suggestive of gastric damage in healthy school-aged children: A case-control study. Int J Infect Dis. 2021 Feb;103:423-430. doi: 10.1016/j.ijid.2020.11.202. Epub 2020 Dec 2. Erratum In: Int J Infect Dis. 2021 Jul;108:125.

• Responsible Party: Miguel O'Ryan Gallardo, Medical Doctor, Pediatrician, Infectious Diseases Specialist. Full Professor., University of Chile
• ClinicalTrials.gov Identifier: NCT05926804
• Other Study ID Numbers: 1220964; 1220964 ( Other Grant/Funding Number: Fondecyt Fondo Nacional de Desarrollo Científico y Tecnológico )
• First Posted: July 3, 2023
• Last Update Posted: January 5, 2024
• Last Verified: January 2024

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Miguel O'Ryan Gallardo, University of Chile:

Helicobacter pylori; Screen and treat; Pepsinogen; Adolescent

Additional relevant MeSH terms:

Amoxicillin; Metronidazole; Clarithromycin; Lansoprazole; Dexlansoprazole; Anti-Bacterial Agents; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Anti-Ulcer Agents; Gastrointestinal Agents; Proton Pump Inhibitors