Clinical trial NCT05926804: A "Screen and Treat" Helicobacter Pylori Eradication Trial in Adolescents in Three Regions of Chile
Official title: A Randomized "Screen and Treat" Helicobacter Pylori Eradication Trial in 14-18 Years Old Adolescents Residing in Three Regions of Chile: Effectiveness and Microbiological-host Implications
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Helicobacter Pylori Infection
Keywords: Helicobacter pylori
Screen and treat
Pepsinogen
Adolescent
Lead sponsor: University of Chile
Sponsor class: OTHER
Collaborators: name: Fondo Nacional de Desarrollo Científico y Tecnológico, Chile
First posted: 2023-07-03
Enrollment: 500
Sex: ALL
Minimum age (years): 14
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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). 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.
Primary purpose: TREATMENT

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 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".

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 up to 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. 210 Subjects with persistent infection 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.

Eligibility 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. Children deemed "not healthy" after review of the questionnaire by study physician

Primary outcomes:
measure: Percentage of persistently-infected teenagers which change UBT status from positive to negative 1 month post-treatment, as compared to non-treated subjects.
timeFrame: a. Baseline: 2 or 3 samples obtained pre-treatment (separated by 30 days) to detect persistently infected children b. One month post-treatment.
measure: 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
timeFrame: a. Baseline evaluation during the month prior to treatment. b. 2-4 months post treatment
measure: 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.
timeFrame: 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
Secondary outcomes:
measure: 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.
timeFrame: 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)]
measure: 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.
timeFrame: 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)]
Other outcomes:
measure: Prevalence of H.pylori persistent infection in adolescents in Colina, Temuco and Aysén
timeFrame: 2 or 3 samples obtained pre-treatment (separated by 30 days) to detect persistently infected children
measure: Effect of treatment on frequency of clarithromycin resistance comparing those subject who would not eradicate with non-treated individuals
timeFrame: a. Baseline: Within 1 month before eradication b.Within 6 months after the positive UBT sample indicating non-eradication or reinfection.
measure: Overall reinfection rates in adolescents with successful eradication after treatment
timeFrame: a. One month post treatment to assess successful eradication b. 6 months after treatment c. Every 6 months up to 24 months post treatment
measure: Change in the percentage of adolescents which have "gastric disease" according to gastroenterologist examination from post eradication to post reinfection.
timeFrame: a. 2-4 months post treatment b. 9-12 months post treatment c. 18-24 months post treatment
measure: Change in blood levels of biomarkers indicative of gastric damage post-reinfection as compared to post-successful eradication.
timeFrame: a. 1 month post treatment b. Within 6 months after the UBT sample indicating reinfection.
measure: Change in gut microbiome alpha-diversity index post-reinfection as compared to post-successful eradication
timeFrame: a. 1 month post treatment b. Within 6 months after the UBT sample indicating reinfection
measure: Change in faecal Escherichia coli and Enterococcus antimicrobial resistance rates post-reinfection as compared to post-successful eradication.
timeFrame: a. 1 month post treatment b. Within 6 months after the UBT sample indicating reinfection
Locations:
city: Coyhaique
country: Chile
facility: Universidad de Aysén
city: Santiago
country: Chile
facility: Universidad de Chile
city: Temuco
country: Chile
facility: Universidad de la Frontera
Study officials:
affiliation: University of Chile
name: Miguel O'Ryan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: Lucero Y, Lagomarcino AJ, Torres JP, Roessler P, Mamani N, George SA, Huerta N, Gonzalez M, O'Ryan G M. Effect of Helicobacter pylori eradication therapy on clinical and laboratory biomarkers associated with gastric damage in healthy school-aged children: A randomized non-blinded trial. Helicobacter. 2021 Dec;26(6):e12853. doi: 10.1111/hel.12853. Epub 2021 Sep 15.