Clinical trial NCT04132479: The Epidemiology and Optimal Treatment of Helicobacter Pylori in Myanmar
Official title: Sequential Helicobacter Pylori Eradication Therapy in Myanmar; a Randomized Clinical Trial of Efficacy and Tolerability
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Helicobacter Pylori Infection
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
Collaborators: name: University of Medicine 2, Yangon, Myanmar
First posted: 2019-10-18
Enrollment: 313
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised control trial
Primary purpose: TREATMENT

Brief summary: This study aims to:

1. Determine the prevalence of Helicobacter infection in Myanmar (this would be the largest ever series in the country)
2. Determine the clinical and epidemiological associations of Helicobacter infection in Myanmar
3. Determine the utility of stool antigen testing to diagnose the infection and confirm eradication
4. Compare the relative efficacies of concomitant and sequential therapy
5. Determine the relative efficacies of first, second and third line therapies in Myanmar in 2018

Detailed description: There are very few published studies to examine the prevalence of Helicobacter infection in Myanmar. Two previous studies (both \< 400 participants) suggested that the prevalence was approximately 50% (Myint WJG 2015, Aye MMJ 2015).

The high prevalence of H.pylori is important because gastric adenocarcinoma is the fourth most common cancer in the country (WHO 2014). Gastric cancer has an almost uniformly dismal 5-year survival rates in this resource-limited country and is estimated to kill almost 5000 patients per year in Myanmar (WHO 2014).

In addition, anecdotally there is a significant associated burden of peptic ulcer disease in the country, although there are few published data to examine the issue.

Strategies to diagnose and eradicate H.pylori must be considered in the context that the annual per capita health budget is USD103 (World Bank 2016).

Therapeutic regimens must also consider the issue of antimicrobial resistance, which varies from country to country. There are very few data from Myanmar to guide us and those that are available vary enormously.

In vitro antibiotic resistance by agent

Amoxycillin 0%, 8%, 7%

Metronidazole 33%, 54%,100%

Clarithromycin 0%, 13%, 50%

Levofloxacin 6%, NR, 3%

Tetracycline 0%, NR, NR

Ciprofloxacin 6%, NR NR

Studies: Mahachai 2012, Aye 2005, Aye 2014

However, it is also known that in vitro resistance does not necessarily translate into in vivo failure. Furthermore in a resource poor setting like Myanmar, a strategy of susceptibility guided treatment is not feasible. Indeed, this is not likely to be cost-effective in even wealthy countries (ACG guidelines 2017 and Maastricht consensus guidelines 2017).

The current first line therapy for H.pylori in Myanmar is 10-14 days of concomitant bd PPI + bd Clarithromycin + bd Amoxycillin + bd metronidazole. This regimen contains up to 126 pills (14 days) and costs up to USD16 (14 days). It is likely that 14 days of 4 drug therapy will generate issues with side effects and adherence, although again this has not been examined locally.

Alternatively, a 10-day sequential regimen of 5 days of bd PPI + Amoxycillin, then 5 days of bd PPI + Clarithromycin and Tinidazole reduces the pill load to 50 pills and the total drug cost to USD6. This regimen has been shown to be highly effective in Slovenia (94.2%), Portugal (90%), Belgium (90%), Israel (95.9%), Thailand (94%), Taiwan (91.9%), Singapore (90.3%), and the United Arab Emirates (88.6%) (Review, De Francesco 2017).

A sequential regimen has been shown to have less satisfactory success rates in Greece , Spain, Ireland, Turkey, Iran, Korea, China, and Puerto Rico (although in many of these studies, metronidazole was used instead of tinidazole (Review, De Francesco 2017)).

The current second-line regimen in Myanmar is 10-14 days of bd PPI + Levofloxacin + Amoxycillin (pill load 80 pills for 10 days, total cost USD3). In this era of evolving drug resistance, we may not want to use quinolones as first line therapy however.

The current third line therapy is Bismuth based quadruple therapy (BQT). This regimen is comprised of Bismuth + PPI + Tetracycline + Tinidazole (pill load 120 pills, total cost USD50)

The proposed study aims to demonstrate that a 10-day course of sequential therapy is not inferior to 14 days of 4 drug concomitant therapy. Assuming a cure rate of 80% for Concomitant 4 drug therapy, and an inferiority bound of 10%, the sample size is 626 (313 patients in each arm). To identify 626 patients, we will need to screen approximately 1250 patients. In this resource-poor setting, diagnosis will be established using monoclonal stool antigen testing (SAT BioMerieux BioNexia). Patients who test positive with SAT will be randomised 1:1 in an open label study to either a 10-day course of sequential therapy or the current first line regimen of concomitant 4 drug therapy. Four weeks after completing therapy, eradication will be confirmed with repeat SAT.

Those patients failing the first line therapy would then receive second line levofloxacin and then tested to confirm eradication. This would determine the efficacy of the country's current second line therapy.

Finally, patients failing first and second line therapy would receive the more involved and expensive third line therapy. Once again, this would determine the efficacy of third line therapy.

To ensure all participants had their H.pylori infection eradicated, those failing three lines of therapy would be offered endoscopy and culture directed therapy.

The performance of the stool antigen test is affected by the PPI therapy, so the study can't easily enrol patients presenting with acute symptoms who will frequently have already been taking PPI therapy (higher rate of false negatives). Therefore, the study will enrol outpatients about to commence aspirin, NSAIDs or anticoagulants (in whom the risk of GI bleeding is higher) or patients with a personal history of peptic ulcer disease or family history of gastric cancer. These are all indications for H.pylori testing (ACG guidelines 2017 and Maastricht consensus guidelines 2017).

Outputs

1. The prevalence of H.pylori in Yangon, Myanmar
2. Clinical and demographic associations of H.pylori infection in Myanmar
3. Efficacy of

   1. Current first line therapy: 14 days of concomitant PPI + amoxy + clari + metro
   2. Alternative: 10 days of sequential PPI + amoxy + clari + Tinidazole
   3. Current second line therapy: 14 days of PPI + Levo + Amoxy
   4. Current third line therapy: 14 days of Bismuth + PPI + tetracycline + metro (BQT)
4. Acceptability - to patients and staff - of stool antigen testing for H.pylori screening and for confirming eradication.

Eligibility criteria: Inclusion Criteria:

* Satisfies one of the criteria for H. pylori testing in the 2017 American College of Gastroenterology guidelines
* Informed consent

Exclusion Criteria:

* No informed consent

Primary outcomes:
measure: Efficacy of sequential Helicobacter Pylori Eradication Therapy versus concomitant Helicobacter Pylori Eradication Therapy.
timeFrame: 4 weeks after completion of initial eradication therapy, at an average of 6 weeks after randomization.
Secondary outcomes:
measure: The number of participants with adverse drug reactions
timeFrame: During therapy with the agents and follow up for the 4 weeks after completion of antibiotic therapy; a total of 6 weeks.
measure: Adherence to therapy
timeFrame: 14 days
Other outcomes:
measure: Loss to follow up
timeFrame: Through study completion, an average of 3 months
measure: Mortality
timeFrame: Through study completion, an average of 3 months
Locations:
city: Yangon
country: Myanmar
facility: Insein General Hospital
Study officials:
affiliation: University of Medicine 2, Yangon, Myanmar
name: Mar Mar Kyi, MD
role: STUDY_CHAIR
References: