Histamine Receptor 2 Antagonists as Enhancers of Anti-Tumour Immunity

• ClinicalTrials.gov Identifier: NCT03145012
• Recruitment Status: Unknown
• First Posted: May 9, 2017
• Last Update Posted: March 11, 2019
• Sponsor: Lisa Barrett
• Collaborators: Nova Scotia Health Authority; Dalhousie University
• Information provided by (Responsible Party): Lisa Barrett, Nova Scotia Health Authority

Study Description

Brief Summary:

The immune response against tumors can be highly effective in preventing tumor development, growth and metastasis under certain circumstances. However, tumor associated immune suppression can profoundly limit the impact of natural tumor immunity and also reduce the effectiveness of tumor immunotherapy strategies.

A major component of tumor associated immune suppression is mediated by myeloid cells, especially the monocytic subset of myeloid derived suppressor cells (MDSC). In recent studies that were conducted through a CCSRI Innovation grant, the investigators discovered that oral treatment of mice with the commonly used histamine receptor 2 (H2) antagonists ranitidine or famotidine inhibits both primary breast tumor development and metastasis, in three distinct mouse tumor models and reduces the numbers of monocytic MDSC. These findings have enormous potential to aid in effective cancer immunotherapy and may have immediate implications for cancer patients.

The objective of this investigation is to determine whether treatment with the H2 receptor antagonist ranitidine alters immune suppression, through modulation of immune cell populations.

The investigators will examine peripheral blood monocyte, neutrophil and NK cell numbers, subsets and activation status from healthy volunteers treated for 6 weeks with daily oral ranitidine.

Ranitidine is widely available and used over the counter in Canada. These drugs are widely recognized as safe, well tolerated and have very few side effects. It has been suggested that among the general population, over 10% of those over the age of 65 take such medications on a regular basis for relief against gastrointestinal discomfort. The outcome of pre-clinical studies in mice warrant further investigation into transferability to humans.

If the outcome of the current proposal proves to be viable, then these drugs could provide a safe method to reduce tumor associated immunosuppression with broad implications, both for current cancer patients and for those at high risk of developing cancer. Further to this, the outcome of our proposal may provide a new strategy for improving the effectiveness of T-cell mediated immunotherapy.

Condition or disease	Intervention/treatment	Phase
Cancer	Drug: Ranitidine	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Healthy individuals will be asked to take ranitidine for 6 weeks to determine the effect on peripheral blood immune cells.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Histamine Receptor 2 Antagonists as Enhancers of Anti-Tumour Immunity
• Actual Study Start Date: May 1, 2018
• Estimated Primary Completion Date: November 1, 2019
• Estimated Study Completion Date: November 1, 2019

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment Group; This is a one arm study in which all individuals receive the treatment; therefore there is no allocation or randomization. Thirty subjects will receive ranitidine to a maximum of 900 mg/day in 2 daily doses for 6 weeks. The dosage target is 8 mg/kg/day, but the range of ranitidine intake will be between 7.5- 9 mg/kg/day. This is due to the formulation of the tablets, sold as 75, 150, and 300mg tablets. The ranitidine will be taken orally.

Drug: Ranitidine; Thirty subjects will receive Ranitidine to a maximum of 900 mg/day in 2 daily oral doses for 6 weeks. The dosage target is 8 mg/kg/day, but the range of ranitidine intake will be between 7.5- 9 mg/kg/day. This is due to the formulation of the tablets, sold as 75, 150, and 300mg tablets.; Other Name: Zantac

Outcome Measures

Primary Outcome Measures :

1. Intra-individual frequency and function of immune cell subsets [ Time Frame: Frequency and function were calculated as the values at 6 wks after treatment compared to the values at baseline. ]
   To determine the effect of histamine 2 receptor antagonists on immune cell function in healthy humans. Frequency and function of B cell, T cell, monocyte, NK cell and MDSC cells will be assessed by flow cytometry and ELISPOT.

Secondary Outcome Measures :

1. Inter-individual frequency and function of immune cell subsets [ Time Frame: Frequency and function were calculated as the values at 6 wks after treatment compared to the values at baseline. ]
   To determine the effect of histamine 2 receptor antagonists on immune cell function cross-sectionally. B cell, T cell, monocyte, NK cell and MDSC cells will be assessed by flow cytometry and ELISPOT.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Age 20-50 years old, all sexes or genders
• Veins acceptable for blood draw
• Able to provide informed consent
• eGFR > 90 mL/min/1.73m2
• Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on physical examination and/or clinical laboratory evaluations (hematology, biochemistry, ECG, urinalysis). Clinical laboratory values within stated normal range; if not within this range, they must be without clinical significance
• Female volunteers who are of childbearing potential that agree to use of the accepted contraceptive regimens from at least 21 days prior to the first administration of study drug, during the study, and for at least 30 days after the last dose of study drug
• Female volunteers who are postmenopausal (no menses for at least 1 year, or surgically sterile

Exclusion Criteria:

• Use of ranitidine for greater than 1 week within 6 months of starting the study
• Medical requirement for ranitidine use
• Current or past diagnosis of: porphyria, cancer, immune deficiency disorder
• Active infection at the time of screening
• Known liver, hematologic, renal disease
• Past history of allergic reaction to ranitidine or past history of hypersensitivity to any ingredient in the formulation or past history of hypersensitivity to other drugs
• Pregnant, planning to be pregnant, or breastfeeding during the study period
• Weight (kg) exceeds 109kg

Contacts and Locations

Locations

Canada, Nova Scotia

Nova Scotia Health Authority

Halifax, Nova Scotia, Canada, B3H 1V7

Sponsors and Collaborators

Lisa Barrett

Nova Scotia Health Authority

Dalhousie University

Investigators

• Principal Investigator: Lisa Barrett, MD/PhD; Nova Scotia Health Authority

More Information

• Responsible Party: Lisa Barrett, Associate Professor, Nova Scotia Health Authority
• ClinicalTrials.gov Identifier: NCT03145012
• Other Study ID Numbers: SAIL-002
• First Posted: May 9, 2017
• Last Update Posted: March 11, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: There is no plan to share the IPD with other researchers.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Lisa Barrett, Nova Scotia Health Authority:

Cancer; Immunity; Peripheral Blood Mononuclear Cells; Ranitidine

Additional relevant MeSH terms:

Ranitidine; Ranitidine bismuth citrate; Anti-Ulcer Agents; Gastrointestinal Agents; Histamine H2 Antagonists; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs