A Randomized Multi-Intervention Trial to Inhibit Precancerous Gastric Lesions in Lingu, Shandong Province

Randomized Multi-Intervention Trial to Inhibit Precancerous Gastric Lesions in Lingu, Shandong Province, China

The Division of Cancer Epidemiology and Genetics is conducting a collaborative randomized multi-intervention trial with the Beijing Institute for Cancer Research to evaluate the etiologic role of Helicobacter pylori, garlic, and certain micronutrients in the multi-step process of gastric carcinogenesis. The primary endpoint will not be cancer, but rather the precancerous lesions severe chronic atrophic gastritis, intestinal metaplasia, and dysplasia. The study is designed to detect a stabilizing or mild decrease in the expected age-related progression of precancerous lesions over the course of the trial. Thus the trial can be considered a study of the potential inhibitors of the process of gastric carcinogenesis. The trial will also provide an evaluation of therapy for H. pylori, including an assessment of reinfection rates, a critical need for formulating strategies for infection control in China and other developing countries. Participating in the trial are approximately 3400 adults aged 35-70 who were part of an ongoing survey of precancerous gastric lesions in 13 Linqu villages in Shandong Province. Linqu appears to be an ideal setting for the trial since stomach cancer rates are among the highes in the world, precancerous gastric lesions are prevalent, and the population is stable and well characterized. These individuals will be randomly assigned (taking H. pylori positivity into account) into 8 intervention groups according to a 2(3) factorial design. The interventions are: 1) initial treatment of H. pylori infection with ameprazole and amoxicillin followed by 2) daily supplementation with a combination of alpha-tocopherol, vitamin C, and selenium; and 3) daily supplementation with garlic extracts. No serious side effects have been seen from any of the interventions to date. The study staff will continue to monitor for possible adverse reactions and the population will receive routine medical care follow-up throughout the course of the trial.

As part of the ongoing study in Linqu, all participants received an endoscopic exam in the fall of 1994. Repeat gastroscopic exams with biopsies at 7 standard gastric sites will be conducted during March to May, 1999 and March to May, 2003 to detect early cancers and to evaluate gasatric mucosal status. The subjects will be categorized according to the most advanced lesions detected in all biopsies and assigned a severity score. The three major endpoints for analysis will be: 1) prevalence of dysplasia or cancer 2) prevalence of sever chronic atrophic gastritis, intestinal metaplasia, dysplasia, or cancer; and 3) average severity score.

Study Overview

• Status: Completed
• Conditions: Precancerous Gastric Lesions
• Intervention / Treatment: Drug: Amoxicillin/omeprazole

Detailed Description

The Division of Cancer Epidemiology and Genetics is conducting an 8-year collaborative randomized multi-intervention trial with the Beijing Institute for Cancer Research to evaluate the etiologic role of Helicobacter pylori, garlic, and certain micronutrients in the multi-step process of gastric carcinogenesis. The primary endpoint will not be cancer, but rather the precancerous lesions severe chronic atrophic gastritis, intestinal metaplasia, and dysplasia. The study is designed to detect a stabilizing or mild decrease in the expected age-related progression of precancerous lesions over the course of the trial. Thus the trial can be considered a study of the potential inhibitors of the process of gastric carcinogenesis. The trial will also provide an evaluation of therapy for H. pylori, including an assessment of reinfection rates, a critical need for formulating strategies for infection control in China and other developing countries. Participating in the trial are approximately 3400 adults aged 35-70 who were part of an ongoing survey of precancerous gastric lesions in 13 Linqu villages in Shandong Province. Linqu appears to be an ideal setting for the trial since stomach cancer rates are among the highest in the world, precancerous gastric lesions are prevalent, and the population is stable and well characterized. These individuals will be randomly assigned (taking H. pylori positivity into account) into 8 intervention groups according to a 2(3) factorial design. The interventions are: 1) initial treatment of H. pylori infection with omeprazole and amoxicillin followed by 2) daily supplementation with a combination of alpha-tocopherol, vitamin C, and selenium; and 3) daily supplementation with garlic extracts. Compliance was excellent and no serious side effects were seen from any of the interventions.

As part of the ongoing study in Linqu, all participants received an endoscopic exam in the fall of 1994. Repeat gastroscopic exams with biopsies at 7 standard gastric sites conducted during March to May, 1999 and March to April, 2003 to detect early cancers and to evaluate gastric mucosal status. The subjects will be categorized according to the most advanced lesions detected in all biopsies and assigned a severity score. The three major endpoints for analysis will be: 1) prevalence of dysplasia or cancer 2) prevalence of severe chronic atrophic gastritis, intestinal metaplasia, dysplasia, or cancer; and 3) average severity score.

The major endpoint paper was published in JNCI in 2006. Additional analyses of the trial data are underway. A continuation study is proceeding that will allow for follow-up of the approximately 3070 remaining trial participants through 2010 on the long-term effects of the previous treatments on gastric cancer incidence and on cause-specific death rates and allow approximately 364 participants in the previous study with advanced gastric lesions in 2003 an opportunity for annual endoscopic screening for gastric cancer.

• Study Type: Interventional
• Enrollment (Actual): 3411
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Beijing Institute for Cancer Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Ages 35-670 in the 14 Linqu villages who received endoscopy examinations in the fall of 1994.

Both men and women will be included.

Patients must sign an informed consent form indicating a willingness to participate in the 42-month trial.

Must be free of debilitating chronic disease.

Must not report allergies to penicillin or similar medications.

Must not have had previous treatment for H. pylori.

Must not have a history of bleeding disorder.

Must not be taking vitamin/mineral supplements on a regular basis.

EXCLUSION CRITERIA:

Persons with cancer (except resected non-melanotic skin cancer), heart failure, emphysema, and other life-threatening illness will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amox/omepr; 2 weeks; placebo controlled	Drug: Amoxicillin/omeprazole; To treat Helicobacter pylori infections. 2 week course of amoxicillin 1gm bid, omeprazole 20mg bid. This factorial trial also investigated a supplement of vitamin C, vitamin E and selenium and a garlic supplement.
Experimental: Garlic; Supplement for 7 years; placebo controlled	Drug: Amoxicillin/omeprazole; To treat Helicobacter pylori infections. 2 week course of amoxicillin 1gm bid, omeprazole 20mg bid. This factorial trial also investigated a supplement of vitamin C, vitamin E and selenium and a garlic supplement.
Experimental: Vitamins; Supplement for 7 years; placebo controlled	Drug: Amoxicillin/omeprazole; To treat Helicobacter pylori infections. 2 week course of amoxicillin 1gm bid, omeprazole 20mg bid. This factorial trial also investigated a supplement of vitamin C, vitamin E and selenium and a garlic supplement.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Precancerous gastric lesions	prevention of cancer	7 years
Gastric cancer incidence	prevention of caner	15 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Side effects	7 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mitchell H Gail, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992 Dec 15;52(24):6735-40.
• You WC, Blot WJ, Chang YS, Ershow AG, Yang ZT, An Q, Henderson B, Xu GW, Fraumeni JF Jr, Wang TG. Diet and high risk of stomach cancer in Shandong, China. Cancer Res. 1988 Jun 15;48(12):3518-23.
• You WC, Blot WJ, Li JY, Chang YS, Jin ML, Kneller R, Zhang L, Han ZX, Zeng XR, Liu WD, et al. Precancerous gastric lesions in a population at high risk of stomach cancer. Cancer Res. 1993 Mar 15;53(6):1317-21.
• Guo Y, Li ZX, Zhang JY, Ma JL, Zhang L, Zhang Y, Zhou T, Liu WD, Han ZX, Li WQ, Pan KF, You WC. Association Between Lifestyle Factors, Vitamin and Garlic Supplementation, and Gastric Cancer Outcomes: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2020 Jun 1;3(6):e206628. doi: 10.1001/jamanetworkopen.2020.6628.
• Li WQ, Zhang JY, Ma JL, Li ZX, Zhang L, Zhang Y, Guo Y, Zhou T, Li JY, Shen L, Liu WD, Han ZX, Blot WJ, Gail MH, Pan KF, You WC. Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: follow-up of a randomized intervention trial. BMJ. 2019 Sep 11;366:l5016. doi: 10.1136/bmj.l5016.

Study record dates

Study Major Dates

• Study Start: July 1, 1995
• Primary Completion (Actual): June 10, 1996
• Study Completion (Actual): June 10, 1996

Study Registration Dates

• First Submitted: June 19, 2006
• First Submitted That Met QC Criteria: June 19, 2006
• First Posted (Estimate): June 21, 2006

Study Record Updates

• Last Update Posted (Actual): December 12, 2019
• Last Update Submitted That Met QC Criteria: December 11, 2019
• Last Verified: February 19, 2019

More Information

Terms related to this study

• Keywords: Helicobacter Pylori; Precancerous Gastric Lesions; Gastric Cancer Prevention
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Bacterial Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Amoxicillin; Omeprazole
• Other Study ID Numbers: 999995029; OH95-C-N029