Helicobacter Eradication Aspirin Trial (HEAT)

Helicobacter Eradication to Prevent Ulcer Bleeding in Aspirin Users: a Large Simple Randomised Controlled Trial

HEAT (Helicobacter Eradication Aspirin Trial) is a large simple double-blind placebo controlled outcomes study of Helicobacter pylori (H. pylori) eradication to prevent ulcer bleeding in aspirin users. It will be run by the University of Nottingham, with recruiting centres across the UK. This trial is funded by the National Institute of Health Research Health Technology Assessment (NIHR HTA) Programme.

Aspirin use is widespread and increasing in elderly patients. The main hazard is gastrointestinal bleeding, which may be increasing because of increasing aspirin use. This trial is based on evidence that peptic ulcer bleeding in aspirin users occurs predominantly in H. pylori positive people.

Patients will be identified by their GPs, then asked to attend an appointment with a Research Nurse to consent to the trial and take a H. pylori breath test. Those with a positive result will be randomised to receive a one week course of either eradication treatment or placebo. No follow-up visits are required, but instead information will be extracted from the patients' electronic medical record using the MiQuest search tool.

The trial will continue until 87 adjudicated events (hospitalisation because of definite or probable peptic ulcer bleeding) have occurred, which would occur after a mean 2.5 patient years of follow-up, if trial assumptions are correct.

Study Overview

• Status: Completed
• Conditions: Bacterial Infection Due to Helicobacter Pylori (H. Pylori); Gastrointestinal Ulcer Haemorrhage
• Intervention / Treatment: Drug: Lansoprazole 30mg, Clarithromycin 500mg, Metronidazole 400mg; Drug: Placebo lansoprazole 30mg, clarithromycin 500mg, metronidazole 400mg

Detailed Description

BACKGROUND: Aspirin use is widespread and increasing in elderly patients. The main hazard is gastrointestinal bleeding, the incidence of which is rising, probably because of increased aspirin use. The proposed trial is based on evidence that peptic ulcer bleeding in aspirin users occurs predominantly in people infected with the ulcerogenic bacterium, Helicobacter pylori. Our hypothesis is that low doses of aspirin do not cause ulcers in the way that high doses do. Instead we think that H. pylori causes the ulcer and aspirin, by thinning the blood, makes it bleed. If the bacterium is eradicated the patient will not get an ulcer and therefore there is no increased bleeding risk with aspirin. Development of the trial protocol has been based on results of a preparatory Medical Research Council-funded 2525 patient pilot study which had a 47% patient response rate. This enabled us to design the currently proposed large simple outcomes study to investigate directly the hypothesis that a one week course of H. pylori eradication will halve the rate of hospitalisation due to ulcer bleeding over ~2.5 years in aspirin users.

TRIAL CONDUCT: A large number of patients (~170,000), using aspirin <326 mg daily will be invited to participate. Suitable respondents (~33,000) who are H. pylori positive (~6,600) will give consent (including access to Hospital Episode Statistics and Office of National Statistics mortality data) and be randomised to eradication treatment or placebo. There will be no follow-up trial visits for 90% of patients. Instead the MiQuest tool, developed to interrogate different GP electronic databases, will be used together with direct patient notification to identify all possible ulcer bleeding admissions. An expert panel will use validated methodology to adjudicate whether patients have suffered ulcer bleeding (primary endpoint). The trial will continue until 87 positively adjudicated events have occurred, to ensure it has the power to answer the question of whether H. pylori eradication reduces the risk of ulcer bleeding.

• Study Type: Interventional
• Enrollment (Actual): 30024
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Belfast, United Kingdom, BT9 7HR
    • Queen's University
  • Birmingham, United Kingdom, B15 2TT
    • University of Birmingham
  • Durham, United Kingdom, TS17 6BH
    • Durham University
  • Nottingham, United Kingdom, NG7 2UH
    • University of Nottingham
  • Oxford, United Kingdom, OX1 2ET
    • University of Oxford
  • Southampton, United Kingdom, SO16 5ST
    • University of Southampton

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females ≥ 60 years of age at the date of screening.
• Subjects who are taking aspirin ≤325mg daily and who have had 4 or more 28-day prescriptions in the last year.
• Subjects who are concurrently using other anti-platelet agents are allowed to enter the study.
• Subjects who are willing and able to undergo a breath test for H. pylori, including fasting for 6 hours, and whose result is unequivocally positive (results of breath test will be determined post-screening).
• Subjects who are willing to give permission for their paper and electronic medical records to be accessed and abstracted by trial investigators.
• Subjects who are willing to be contacted and interviewed by trial investigators, should the need arise for adverse event assessment, etc.
• Subjects must be able to communicate well with the investigator or designee, to understand and comply with the requirements of the study and to understand and sign the written informed consent.

Exclusion Criteria:

• Subjects who are currently prescribed anti-ulcer therapy such as H2-receptor antagonists and proton-pump inhibitors.
• Subjects who are currently prescribed oral non-steroidal anti-inflammatory drugs (NSAIDs).
• Subjects who have a known intolerance or allergy to H. pylori eradication treatment.
• Subjects who are taking drugs with a clinically significant interaction with H. pylori eradication treatment.
• Subjects who are terminally ill or suffer from a life-threatening co-morbidity.
• Subjects whose behaviour or lifestyle would render them less likely to comply with study medication (eg. alcoholism, substance abuse, debilitating psychiatric conditions or inability to provide informed consent).
• Subjects currently participating in another interventional clinical trial or who have taken part in a trial in the previous three months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: H. pylori eradication treatment; Active treatment will consist of seven days of lansoprazole 30mg twice daily, clarithromycin 500mg twice daily and metronidazole 400mg twice daily.	Drug: Lansoprazole 30mg, Clarithromycin 500mg, Metronidazole 400mg; All three medications will be taken orally, twice daily, for seven days.; Other Names: Lansoprazole (CAS: 103577-45-3); 30mg capsules.; Clarithromycin (CAS: 81103-11-9); 500mg tablets.; Metronidazole (CAS: 99616-64-5) 400mg tablets.
PLACEBO_COMPARATOR: Placebo H. pylori eradication treatment; Placebos to seven days of lansoprazole 30mg twice daily, clarithromycin 500mg twice daily and metronidazole 400mg twice daily.	Drug: Placebo lansoprazole 30mg, clarithromycin 500mg, metronidazole 400mg; Medication to be taken orally, twice a day, for seven days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The rate of hospitalisation due to peptic ulcer bleeding in patients who enter the randomised study (only the first event per patient will be analysed), adjudicated by a blinded Committee as definite or probable.	4 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Other causes of gastrointestinal bleeding (adjudicated); these are predicted not to be affected by H. pylori eradication and will act as a specificity control.	4 years
Cardiovascular outcomes (APTC (Anti Platelet Trialists Collaboration) endpoint, myocardial infarction and stroke, unadjudicated); these are predicted not to be affected.	4 years
The incidence of detected uncomplicated ulcers.	4 years
Ulcer site (Duodenal Ulcer vs. Gastric Ulcer).	4 years
GP-recorded and patient-reported dyspepsia.	4 years
Need for proton pump inhibitor prescription or other antiulcer/dyspepsia medication.	4 years

Collaborators and Investigators

• Sponsor: University of Nottingham
• Collaborators: University of Oxford; Nottingham University Hospitals NHS Trust; University of Southampton; Queen's University, Belfast; University of Birmingham; University of Durham
• Investigators: Principal Investigator: Chris J Hawkey, University of Nottingham

Publications and helpful links

General Publications

• Dumbleton JS, Avery AJ, Coupland C, Hobbs FD, Kendrick D, Moore MV, Morris C, Rubin GP, Smith MD, Stevenson DJ, Hawkey CJ. The Helicobacter Eradication Aspirin Trial (HEAT): A Large Simple Randomised Controlled Trial Using Novel Methodology in Primary Care. EBioMedicine. 2015 Jul 10;2(9):1200-4. doi: 10.1016/j.ebiom.2015.07.012. eCollection 2015 Sep.
• Stevenson DJ, Avery AJ, Coupland C, Hobbs FDR, Kendrick D, Moore MV, Morris C, Rubin GP, Smith MD, Hawkey CJ, Dumbleton JS. Recruitment to a large scale randomised controlled clinical trial in primary care: the Helicobacter Eradication Aspirin Trial (HEAT). Trials. 2022 Feb 14;23(1):140. doi: 10.1186/s13063-022-06054-w.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2012
• Primary Completion (ACTUAL): October 31, 2017
• Study Completion (ACTUAL): March 16, 2022

Study Registration Dates

• First Submitted: January 5, 2012
• First Submitted That Met QC Criteria: January 5, 2012
• First Posted (ESTIMATE): January 10, 2012

Study Record Updates

• Last Update Posted (ACTUAL): May 17, 2022
• Last Update Submitted That Met QC Criteria: May 16, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Aspirin; Helicobacter pylori; H. pylori; Ulcer bleeding; Hospitalisation for ulcer bleeding
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Bacterial Infections and Mycoses; Ulcer; Hemorrhage; Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Protein Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Metronidazole; Dexlansoprazole; Lansoprazole; Clarithromycin
• Other Study ID Numbers: 11091; 09/55/52 (OTHER_GRANT: NIHR HTA); 2011-003425-96 (EUDRACT_NUMBER); ISRCTN10134725 (REGISTRY: ISRCTN)