Clinical trial NCT06881511: Exploratory Study on the Efficacy of Betaine Hydrochloride in Treating Autoimmune Gastritis
Official title: Exploratory Study on the Efficacy of Betaine Hydrochloride in Treating Autoimmune Gastritis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Autoimmune Gastritis
Keywords: Autoimmune Gastritis
Iron-Deficiency Anemia
Stomach Neoplasms
Neuroendocrine Tumors
Betaine
Hydrochloride
Pepsin
Gastrointestinal Agents
Gastrins
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
First posted: 2025-03-18
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will employ a linear mixed-effects model to analyze changes in primary outcomes (GSRS scores and serum gastrin levels), with the intervention effect evaluated through group-by-time interactions. For secondary outcomes, continuous variables will be analyzed using multiple linear regression, while categorical variables will be analyzed using logistic regression or Cox proportional hazards models. All models will adjust for baseline differences (via propensity score matching) and potential confounders. Model assumptions will be validated through residual analysis and diagnostic plots. Sensitivity analyses will include per-protocol vs intention-to-treat comparisons and alternative propensity score methods. Data analysis will be performed using R (version 4.0) or SAS (version 9.4).
Primary purpose: TREATMENT

Brief summary: Autoimmune gastritis (AIG) is a chronic autoimmune disorder characterized by parietal cell destruction and oxyntic mucosal atrophy, leading to achlorhydria and intrinsic factor deficiency. These pathological changes impair iron and vitamin B12 absorption, resulting in iron-deficiency anemia, pernicious anemia, and neuropsychiatric manifestations. Notably, 4-12% of AIG patients develop type 1 gastric neuroendocrine tumors, while facing a 3-7 fold increased risk of gastric adenocarcinoma with an incidence of 0.9-9%.

Current management of AIG is limited to iron and vitamin B12 replacement, as no disease-modifying therapies exist. The progressive hypochlorhydria reduces pepsin activity, impairs gastric motility, and promotes small intestinal bacterial overgrowth (SIBO), causing dyspeptic symptoms and micronutrient malabsorption. Furthermore, gastric hypoacidity increases N-nitroso compound formation and triggers hypergastrinemia, elevating risks for both gastric cancer and neuroendocrine tumors.

This clinical trial investigates whether betaine hydrochloride (with pepsin) supplementation can restore gastric acidity and improve clinical outcomes in AIG. We will evaluate its effects on gastrin levels, gastrointestinal symptoms, exhaled gas markers (NO, H₂S, H₂, CH₄), anemia parameters, endoscopic atrophy scores, and incidence of gastric complications (hyperplastic polyps, neuroendocrine tumors, and adenocarcinoma). The study aims to provide evidence for a potential therapeutic strategy addressing both symptoms and long-term complications of AIG.

Detailed description: Autoimmune gastritis (AIG) is a chronic progressive autoimmune disorder characterized by the destruction of gastric parietal cells, leading to atrophy of the acid-secreting gastric mucosa. The loss of parietal cells results in gastric acid deficiency and intrinsic factor deficiency, which in turn impairs the absorption of iron and vitamin B12, leading to clinical manifestations such as iron deficiency anemia, pernicious anemia, and neuropsychiatric symptoms. Studies indicate that 4-12% of AIG patients develop type 1 gastric neuroendocrine tumors (NETs), and these patients also face a 3-7 times higher risk of gastric adenocarcinoma, with an incidence rate ranging from 0.9% to 9%.

Currently, there are no anti-inflammatory, immunosuppressive, or biologic therapies available for AIG. Standard treatment involves iron and vitamin B12 supplementation. Due to progressive parietal cell destruction, AIG patients exhibit a hypochlorhydric state, which reduces pepsin activity, impairs gastric motility, and may lead to small intestinal bacterial overgrowth (SIBO), often causing symptoms such as dyspepsia. Additionally, low gastric acid levels can interfere with the absorption of trace elements like iron and calcium. Insufficient gastric acid also promotes bacterial overgrowth in the stomach and increases N-nitroso compounds, elevating the risk of gastric cancer. Furthermore, gastric hypochlorhydria triggers a feedback mechanism that stimulates gastrin secretion from antral G cells, resulting in hypergastrinemia, which increases the risk of neuroendocrine tumors. Supplementation with betaine hydrochloride (with pepsin) can lower gastric pH in AIG patients, restore gastric acidity, improve protein digestion, alleviate dyspeptic symptoms, enhance the absorption of vitamins and minerals, correct gastric dysbiosis and SIBO, and reduce the risk of gastric cancer and neuroendocrine tumors.

This study aims to evaluate the effects of betaine hydrochloride (with pepsin) on gastrin levels, gastrointestinal symptoms, exhaled gas markers (NO, H2S, H2, and CH4), iron deficiency anemia parameters, AIG atrophy scores, and the incidence of gastric complications (hyperplastic polyps, neuroendocrine tumors, and gastric cancer). The study is divided into two groups: Group A (follow-up only, serving as the control group) and Group B (oral betaine hydrochloride). The study adopts a non-randomized, open-label, parallel-controlled design, where participants choose either the experimental group (oral betaine) or the control group (follow-up only) based on their preference. Both groups will be followed in parallel, and outcome differences will be compared, supplemented by within-group pre- and post-intervention analyses.

The study population consists of AIG patients diagnosed at the Second Affiliated Hospital of Zhejiang University School of Medicine. The diagnostic criteria for AIG are based on our team's published article in Clinics and Research in Hepatology and Gastroenterology: "A real-world study on the characteristics of autoimmune gastritis: A single-center retrospective cohort in China." Inclusion criteria include: serum gastrin levels \>300 pmol/L or a history of type 1 gastric NETs or early gastric cancer treated with endoscopic submucosal dissection (ESD), age between 18 and 80 years, and signed informed consent. Exclusion criteria include: allergy to betaine hydrochloride, presence of peptic ulcers, other conditions causing elevated gastrin levels, and refusal to sign informed consent.

Group A (control group) will undergo follow-up only without intervention, while Group B will receive oral betaine hydrochloride (2 capsules three times daily with meals). The primary outcomes include changes in serum gastrin levels and improvements in the Gastrointestinal Symptom Rating Scale (GSRS). Secondary outcomes include changes in iron deficiency anemia markers (serum iron, ferritin, hemoglobin), exhaled gas markers (NO, H2S, H2, CH4), AIG atrophy scores, and the incidence of gastric complications (hyperplastic polyps, NETs, and gastric cancer).

Data will be collected through questionnaires, laboratory tests, endoscopy, and pathological records, with propensity score matching (PSM) used to adjust for baseline differences. The study has been approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. Adverse events will be monitored regularly, and serious adverse events will be reported promptly to the ethics committee and regulatory authorities.

This study will provide critical evidence on the efficacy and safety of betaine hydrochloride in treating AIG, exploring a simple, cost-effective therapeutic approach to alleviate symptoms and reduce the risk of severe complications.

Eligibility criteria: Inclusion Criteria:

1. Patients diagnosed with autoimmune gastritis at the Second Affiliated Hospital of Zhejiang University School of Medicine, with the diagnostic criteria for autoimmune gastritis based on the article "A real-world study on the characteristics of autoimmune gastritis: A single-center retrospective cohort in China" published by our team in the journal Clinics and Research in Hepatology and Gastroenterology;
2. Gastrin levels greater than 300 pmol/L or a history of type 1 gastric neuroendocrine tumors or early gastric cancer treated with endoscopic submucosal dissection (ESD);
3. Age between 18 and 80 years;
4. Patients who have signed the informed consent form for the clinical trial.

Exclusion Criteria:

1. Patients allergic to betaine hydrochloride;
2. Patients with peptic ulcers;
3. Patients with any condition other than autoimmune gastritis that causes elevated gastrin levels (e.g., gastrinoma);
4. Patients who refuse to sign the informed consent form.

Primary outcomes:
measure: Serum Gastrin Levels
timeFrame: Baseline, 1 month, 3 months, 7 months, and 12 months.
measure: Gastrointestinal Symptom Scores
timeFrame: Baseline, 1 month, 3 months, 7 months, and 12 months.
Secondary outcomes:
measure: Exhaled Gas Markers (NO, H2S, H2, and CH4)
timeFrame: Baseline, 1 month, and 12 months.
measure: Iron Deficiency Anemia Indicators (Serum Iron, Ferritin, Hemoglobin)
timeFrame: Baseline, 1 month, and 12 months.
measure: AIG Atrophy Score and Incidence of Gastric Complications
timeFrame: Baseline and 12 months.
Other outcomes:
Locations:
city: Hangzhou City
country: China
facility: The Second Affiliated Hospital, Zhejiang University School of Medicine
state: Zhejiang
Study officials:
References:
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