Selenium and Arsenic Pharmacodynamics

Arsenic Poisoning Chronic Clinical Trial

— SEASP  

Official title:

Selenium and Arsenic Pharmacodynamics

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02377635
• Other study ID #: 14-284
• Secondary ID: Grand Challenges
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: February 10, 2015
• Last updated: October 26, 2017
• Start date: February 10, 2015
• Est. completion date: January 19, 2017

Study information

• Verified date: October 2017
• Source: University of Saskatchewan
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This clinical trial should prove that selenium can treat arsenic exposure in humans by promoting excretion. The new trial differs from previous trials in that participants will be maintained in a local clinic and provided with food and water from their home villages. The purpose of this study to determine the fate of selenium supplements in feces, urine and blood of volunteers living in conditions of high arsenic load in drinking water. The use of a clinic will enable monitoring of all intake and excretion of both arsenic and selenium, and will ensure that participants take their selenium doses or placebo as appropriate. This proof of concept is absolutely essential groundwork for any remediation strategy involving selenium supplements.

Description:

Main Purpose:

Determine the fate of selenium supplements in feces, urine and blood through a new Phase I/II clinical trial pharmacodynamics study in Bangladesh. This will include conventional analysis of feces, urine and blood samples, tracing the fate of selenium by administering isotopically enriched 77Se (a naturally occurring non-radioactive stable isotope). The use of 77Se will allow us to discriminate between endogenous selenium already in the bodies of the trial participants (patients) from the administered selenium given to the patients.

Clinical Trial Hypotheses:

• In a group of patients exhibiting symptoms of arsenicosis (chronic low-level arsenic poisoning), a single, elevated dose of anhydrous sodium selenite leads to excretion of arsenic at levels significantly higher than patients receiving placebo.

• In the selenite-supplemented (treatment) group, the total arsenic excreted is significantly higher than that consumed in the diet and drinking water.

• In the treatment group, selenium co-excreting with arsenic originates from the administered selenium supplement, rather than from endogenous selenium.

• The ratio of arsenic to selenium in the feces, urine and blood of the treatment group following administration of the selenium supplement is approximately 1:1, consistent with the formation of the discrete molecular entity, the seleno bis-S-glutathionyl arsinium anion discovered in the investigators' earlier animal experiments.

The process to be followed:

A tightly controlled Phase I/II clinical trial in Bangladesh to prove that selenium can remove arsenic from victims' bodies. 40 volunteer arsenicosis sufferers will be housed in a local private in-patient clinic for 10 consecutive days. While in the clinic, they will follow a fixed, communal diet consisting of drinking water and meals from their village. On the 6th day in the clinic investigators will give a single dose of either placebo (table salt, 0.8 mg) or anhydrous sodium selenite (0.8 mg selenium) labelled with a non-radioactive naturally occurring isotope (77Se), to distinguish it from selenium already in the body. Placebo and anhydrous sodium selenite look similar and taste very much alike. Placebo or anhydrous sodium selenite will be supplied in a powdered form at the bottom of a glass and diluted by 100 ml of purified water immediately before being ingested by participants under close control by the clinical staff. The investigators will analyze arsenic and selenium levels in feces, urine and blood samples before and after the dose, and will use molecular speciation analyses to determine their chemical form in blood, urine and feces. Also, investigators will analyze arsenic and selenium levels in finger- and toenails and hair at the beginning of the trial as a possible biomarker of As exposure.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: January 19, 2017
• Est. primary completion date: December 19, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

The participants in this study are

1. healthy adult (18-65 years of age) male Bangladeshi volunteers from Laksam Upazila,

2. who are exposed to arsenic through their normal source of drinking water;

3. who are otherwise healthy except that show some signs of chronic arsenic toxicity (arsenicosis);

4. have not consumed selenium-containing supplements with last 6 months;

5. not concurrently participating or have participated in any other clinical trial within at least 30 days of registration to the current trial.

Exclusion Criteria:

1. Recent history of consuming selenium, concurrent participation or recent participation in any other clinical trial within at least 30 days of registration to the current trial, and people who recently moved in the area.

2. Prior clinical trial, recruits will undertake a medical examination by physician. Since chronic kidney disease and alcoholic and viral cirrhosis are common in rural Bangladesh and both conditions might impact selenium and arsenic metabolism, recruits will also be screened through a baseline CMP (Comprehensive Metabolic Panel) , CBC (Complete Blood Count), and INR (International Normalized Ratio of Prothrombin Time as Liver Function Test) panel. Evidence or history of significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, musculoskeletal, immunologic, neurologic or dermatologic disease (including drug allergies that are clinically significant) which, by opinion of investigators, could pose a risk to the safety of the individual or the valid conduct of the study will exclude recruits from the participation.

3. Current evidence of or history of cancer; evidence of hepatitis B, hepatitis C, human immunodeficiency virus (HIV) infection upon serological testing; evidence of active communicable disease or febrile illness (e.g., bronchopulmonary, urinary or gastrointestinal) within 7 days prior to study will exclude recruits from participation.

Related Conditions & MeSH terms

• Arsenic Poisoning
• Arsenic Poisoning Chronic
• Poisoning

Intervention

Dietary Supplement:
• Anhydrous selenite
40 volunteer sufferers will be housed in a local private in-patient clinic where they will follow a fixed, communal diet consisting of drinking water and meals from their village. On a 6th day we will give a single dose of placebo (sodium chloride) or anhydrous sodium selenite (0.8mg selenium) labelled with a non-radioactive naturally occurring isotope (77Se), to distinguish it from selenium already in the body.
• Sodium chloride
40 volunteer sufferers will be housed in a local private in-patient clinic where they will follow a fixed, communal diet consisting of drinking water and meals from their village. On a 6th day we will give a single dose of placebo (sodium chloride) or anhydrous sodium selenite (0.8mg selenium) labelled with a non-radioactive naturally occurring isotope (77Se), to distinguish it from selenium already in the body.

Locations

Country	Name	City	State
Bangladesh	Unity Hospital Pvt LTD	Laksam	Comilla

Sponsors (7)

Lead Sponsor	Collaborator
University of Saskatchewan	Applied Speciation and Consulting LLC, WA, USA, Emory University, University of Alberta, University of Calgary, University of Chicago, Wagner College, Staten Island, NY, USA

Country where clinical trial is conducted

Bangladesh, 

References & Publications (4)

Carew MW, Leslie EM. Selenium-dependent and -independent transport of arsenic by the human multidrug resistance protein 2 (MRP2/ABCC2): implications for the mutual detoxification of arsenic and selenium. Carcinogenesis. 2010 Aug;31(8):1450-5. doi: 10.1093/carcin/bgq125. Epub 2010 Jun 27. — View Citation

Gailer J, George GN, Pickering IJ, Prince RC, Younis HS, Winzerling JJ. Biliary excretion of [(GS)(2)AsSe](-) after intravenous injection of rabbits with arsenite and selenate. Chem Res Toxicol. 2002 Nov;15(11):1466-71. — View Citation

Manley SA, George GN, Pickering IJ, Glass RS, Prenner EJ, Yamdagni R, Wu Q, Gailer J. The seleno bis(S-glutathionyl) arsinium ion is assembled in erythrocyte lysate. Chem Res Toxicol. 2006 Apr;19(4):601-7. — View Citation

Prince RC, Gailer J, Gunson DE, Turner RJ, George GN, Pickering IJ. Strong poison revisited. J Inorg Biochem. 2007 Nov;101(11-12):1891-3. Epub 2007 Jun 13. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood As and Se concentrations and chemistry	The ICPMS technique will be used to analyze arsenic and selenium levels in blood samples before and after the dose. The molecular speciation analyses (IC-ICP-MS) will be applied to determine their chemical form in blood.	10 days
Primary	Urinary As and Se concentrations and chemistry	The ICPMS technique will be used to analyze arsenic and selenium levels in urine samples before and after the dose. The molecular speciation analyses (IC-ICP-MS) will be applied to determine their chemical form in urine.	10 days
Primary	Fecal As and Se concentrations and chemistry	The ICPMS technique will be used to analyze arsenic and selenium levels in feces samples before and after the dose. The molecular speciation analyses (IC-ICP-MS) will be applied to determine their chemical form in feces.	10 days
Secondary	The absolute concentrations of 77Se and the ratios (total Se/77Se) and (As/77Se) determined in blood, at each time point of the study.	Quantitative analysis (ICP-MS) of As, 77Se and total Se to evaluate the effect of Se supplementation on binding and excretion of arsenic as opposed to the mobilization of endogenous Se in a body.	10 days
Secondary	The absolute concentrations of 77Se and the ratios (total Se/77Se) and (As/77Se) determined in urine, at each time point of the study.	Quantitative analysis (ICP-MS) of As, 77Se and total Se to evaluate the effect of Quantitative analysis (ICP-MS) of As, 77Se and total Se to evaluate the effect of Se supplementation on excretion of arsenic as opposed to the mobilization of endogenous Se in a body.	10 days
Secondary	The absolute concentrations of 77Se and the ratios (total Se/77Se) and (As/77Se) determined in feces, at each time point of the study.	Quantitative analysis (ICP-MS) of As, 77Se and total Se to evaluate the effect of Se supplementation on excretion of arsenic as opposed to the mobilization of endogenous Se in a body.	10 days
Secondary	Arsenic and selenium concentrations in hair, finger- and toenails	Quantitative analysis (ICP-MS) of As and Se content in keratinous tissues as a possible biomarker of As exposure	1 day