NBMI Treatment in Patients With Mercury Toxicity

NCT04183595 | Recruiting Phase 2 DMC

• 1 other identifier: Emera008
• Study Type: interventional
• Target: 116
• Locations: 1 country
• Sites: 1

Brief Summary

NBMI (N1, N3-Bis-(2-Mercaptoethyl) Isophthalamide) is a new metal chelator drug proposed as an alternative to the current chelators, and it is widely different; compared to the current chelators, consisting of two cysteamine molecules coupled to a single molecule of dicarboxybenzoate. It is used as a chelating agent and has the designation of an orphan drug, in the EU and USA; in the EU it is used for the treatment of mercury toxicity. It is freely soluble in solutions of dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and sodium hydroxide diluted NaOH, slightly soluble in methanol and acetone, and insoluble in water. Pre-clinical data indicates low to no toxicity, and that it reduces the toxicity associated with acute exposure to Hg2+. No other chelator has been reported to prevent acute mercury toxicity with only one exposure to the chelator. It has the ability to penetrate cell membranes and cross the blood-brain barrier and chelate Hg2+ in a complex that eliminates the availability of Hg2+ and essentially eliminates toxic effects. The antioxidant properties of NBMI could also reduce the toxicity levels of hydroxyl free radicals immediately, upon entering cells suffering from oxidative stress. It is possible that the combined chelation of Hg2+ and the elimination of hydroxyl free radicals contribute significantly to the protective effects observed with the NBMI. Previous clinical studies conducted in subjects of the Phase I and Phase II a studies conducted, did not show significant adverse events in patients intoxicated with mercury, all patients who received the study medication have tolerated it well, with only mild or moderate adverse events reported; None of these were considered related to the pharmacological treatment of the study. In addition, there is no potential identified with safety problems in laboratory tests, or vital signs evaluations. The purpose of this Controlled Single-Center Double-Blind Crossover Clinical Trial Phase II b is to determine the efficacy, safety and tolerability of a 14 day 600mg / day of NBMI (N1, N2-bis-2-mercaptoethyl isophthalamide) Treatment, in the reduction of urinary mercury levels versus placebo, in accidentally exposed subjects to mercury in Colombia.

Conditions

Mercury Poisoning

Keywords

Exposure to mercury; NBMI

Outcome Measures

Primary Outcomes (1)

• Measure the "Change in the subject's urine mercury levels"

  Evaluation of the difference in mercury levels in the urine as percentage of mercury concentration levels will be determined. The percentage is calculated by comparing baseline mercury concentration levels, against the levels observed at 14-day and 28-days follow-up visits. A rule of three is applied to determine the percentage (%) of change. The analysis of total Hg concentration will be done via Cold Vapor Atomic Absorption spectrometry

  Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment

Secondary Outcomes (9)

• Measure the "Change in the subject's blood iron levels"

  Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment

• Measure the "Change in the subject's blood glucose levels"

  Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment

• Measure the "Change in the subject's renal function"

  Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment

• Measure the "Frequency and Severity of Adverse Events"

  From the first dose of study medication until the Day 56 visit.

• Measure subject's "Variations in Mental Response ".

  Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment

Other Outcomes (2)

• Amalgam

  Baseline (Before) treatment

• Diet

  The patients will keep a food diary during the study (days 1-56).

Study Arms (2)

Arm A: NBMI (Study Medication)

EXPERIMENTAL

600mg / day N1, N3-BIS- (2-MERCAPTOETHYL) ISOPHTHALAMIDE (NBMI) treatment for 14 days, administered as four capsules of 100 mg of NBMI every 24 hours.

Drug: (N1, N3-bis(2- mercaptoethyl)isophthalamide)

Arm B: Placebo

PLACEBO COMPARATOR

(Excipients microcrystalline cellulose, silica and magnesium stearate) capsules will be administered every 24 hours for 14 days.

Other: Excipients microcrystalline cellulose, silica and magnesium stearate

Interventions

(N1, N3-bis(2- mercaptoethyl)isophthalamide) DRUG

600mg / day NBMI treatment for 14 days, administered as four capsules of 100 mg of NBMI every 24 hours, at the start of treatment, the principal investigator or his delegate will verify the intake of the first dose and deliver a blister pack corresponding to the remaining NBMI capsules, at visit day 14 research subjects will be asked to return the packaging with the remaining capsules or not, in order to estimate adherence to treatment.

Also known as: NBMI

Arm A: NBMI (Study Medication)

Excipients microcrystalline cellulose, silica and magnesium stearate OTHER

6 Capsules will be administered every 24 hours for 14 days.

Also known as: Placebo

Arm B: Placebo

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a history of exposure to sources of mercury release by a known event of direct contact with metallic mercury.
• All subjects must have signed and dated an informed consent / assent consent form approved by the IRB in accordance with regulatory and institutional guidelines. This form must be obtained before performing any procedure related to the protocol that is not part of the subject's normal regimen.
• Under age minors must also have a psychological evaluation and documentation of Assent added to the Informed Consent Form.
• Patients with detectable urinary mercury levels \>10 ug / L at the time of screening.
• Patients must be willing and able to comply with clinic visits and all study-related procedures.
• Subjects with no previous chelation treatment or who have stopped receiving chelation treatment for more than 3 months will be enrolled.
• Participants must have controlled mercury levels, with no severe clinical manifestations, regardless of what the medical treatment may have been.

You may not qualify if:

• A history of known or suspected hypersensitivity or idiosyncratic reactions to the medication or test excipients. Patients with sulfa-drug sensitivity should be excluded from this study.
• Levels of mercury in urine / blood at the time of baseline measurement that are below detection threshold.
• Known history of drug addiction and / or alcoholism.
• Patients with a known medical condition that, in the opinion of the investigator, could increase the risk associated with participation in the study or with the administration of the study medication (s) under blinded conditions or interfere with the interpretation of the security results.
• Patients with major surgery or significant traumatic injury who have not recovered at least 14 days before the first dose of the study medications (s) under blind.
• Subjects with a condition requiring systemic corticosteroid therapy (\> 10 mg daily of prednisone equivalent) or other immunosuppressive medications within 14 days before or during treatment are excluded.
• Women with positive pregnancy test (urine sample) at the time of screening; or women who are breastfeeding, or are of childbearing age who disagree with taking contraceptives during treatment and until Day 28 after the last dose.

Sponsors & Collaborators

• EmeraMed: lead

Study Sites (1)

Clínica de la Costa Ltda.

Barranquilla, Atlántico, Colombia

RECRUITING

Related Publications (14)

• Cordy P, Veiga MM, Salih I, Al-Saadi S, Console S, Garcia O, Mesa LA, Velasquez-Lopez PC, Roeser M. Mercury contamination from artisanal gold mining in Antioquia, Colombia: The world's highest per capita mercury pollution. Sci Total Environ. 2011 Dec 1;410-411:154-60. doi: 10.1016/j.scitotenv.2011.09.006. Epub 2011 Oct 15.

  PMID: 22000915 BACKGROUND

• Erkek N, Senel S, Sarac A, Ertan U, Karacan CD. Being alive after a severe inorganic mercury intoxication. Eur J Pediatr. 2010 May;169(5):625-8. doi: 10.1007/s00431-009-1073-2. Epub 2009 Oct 4.

  PMID: 19802724 BACKGROUND

• Khan F, Momtaz S, Abdollahi M. The relationship between mercury exposure and epigenetic alterations regarding human health, risk assessment and diagnostic strategies. J Trace Elem Med Biol. 2019 Mar;52:37-47. doi: 10.1016/j.jtemb.2018.11.006. Epub 2018 Nov 14.

  PMID: 30732897 BACKGROUND

• Zeitz P, Orr MF, Kaye WE. Public health consequences of mercury spills: Hazardous Substances Emergency Events Surveillance system, 1993-1998. Environ Health Perspect. 2002 Feb;110(2):129-32. doi: 10.1289/ehp.02110129.

  PMID: 11836139 BACKGROUND

• Schober SE, Sinks TH, Jones RL, Bolger PM, McDowell M, Osterloh J, Garrett ES, Canady RA, Dillon CF, Sun Y, Joseph CB, Mahaffey KR. Blood mercury levels in US children and women of childbearing age, 1999-2000. JAMA. 2003 Apr 2;289(13):1667-74. doi: 10.1001/jama.289.13.1667.

  PMID: 12672735 BACKGROUND

• Park JD, Zheng W. Human exposure and health effects of inorganic and elemental mercury. J Prev Med Public Health. 2012 Nov;45(6):344-52. doi: 10.3961/jpmph.2012.45.6.344. Epub 2012 Nov 29.

  PMID: 23230464 BACKGROUND

• Ha E, Basu N, Bose-O'Reilly S, Dorea JG, McSorley E, Sakamoto M, Chan HM. Current progress on understanding the impact of mercury on human health. Environ Res. 2017 Jan;152:419-433. doi: 10.1016/j.envres.2016.06.042. Epub 2016 Jul 18.

  PMID: 27444821 BACKGROUND

• Branco V, Caito S, Farina M, Teixeira da Rocha J, Aschner M, Carvalho C. Biomarkers of mercury toxicity: Past, present, and future trends. J Toxicol Environ Health B Crit Rev. 2017;20(3):119-154. doi: 10.1080/10937404.2017.1289834. Epub 2017 Apr 5.

  PMID: 28379072 BACKGROUND

• Clarkson TW, Magos L. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol. 2006 Sep;36(8):609-62. doi: 10.1080/10408440600845619.

  PMID: 16973445 BACKGROUND

• Clarke D, Buchanan R, Gupta N, Haley B. Amelioration of Acute Mercury Toxicity by a Novel, Non-Toxic Lipid Soluble Chelator N,N'bis-(2-mercaptoethyl)isophthalamide: Effect on Animal Survival, Health, Mercury Excretion and Organ Accumulation. Toxicol Environ Chem. 2012;94(3):616-640. doi: 10.1080/02772248.2012.657199.

  PMID: 22573916 BACKGROUND

• Risher JF, Amler SN. Mercury exposure: evaluation and intervention the inappropriate use of chelating agents in the diagnosis and treatment of putative mercury poisoning. Neurotoxicology. 2005 Aug;26(4):691-9. doi: 10.1016/j.neuro.2005.05.004.

  PMID: 16009427 BACKGROUND

• George GN, Prince RC, Gailer J, Buttigieg GA, Denton MB, Harris HH, Pickering IJ. Mercury binding to the chelation therapy agents DMSA and DMPS and the rational design of custom chelators for mercury. Chem Res Toxicol. 2004 Aug;17(8):999-1006. doi: 10.1021/tx049904e.

  PMID: 15310232 BACKGROUND

• Bose-O'Reilly S, Bernaudat L, Siebert U, Roider G, Nowak D, Drasch G. Signs and symptoms of mercury-exposed gold miners. Int J Occup Med Environ Health. 2017 Mar 30;30(2):249-269. doi: 10.13075/ijomeh.1896.00715. Epub 2017 Mar 22.

  PMID: 28366955 BACKGROUND

• Doering S, Bose-O'Reilly S, Berger U. Essential Indicators Identifying Chronic Inorganic Mercury Intoxication: Pooled Analysis across Multiple Cross-Sectional Studies. PLoS One. 2016 Aug 30;11(8):e0160323. doi: 10.1371/journal.pone.0160323. eCollection 2016.

  PMID: 27575533 BACKGROUND

MeSH Terms

Conditions

Mercury Poisoning

Interventions

Silicon Dioxide; stearic acid

Condition Hierarchy (Ancestors)

Heavy Metal Poisoning; Poisoning; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Minerals; Inorganic Chemicals; Oxides; Oxygen Compounds; Silicon Compounds

Study Officials

• Andres Cadena-Bonfanti, MD

  Clínica De La Costa Ltda.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Haley E Boyd, PhD

CONTACT

+1-859-266-92 00 (01); boyd.haley@emeramed.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The research center must assign an unblinded pharmacist or a designated person and a non-blinded CRO monitor, to monitor medication supply and other unblinded documentation of the study. Masking through identical capsules and blister in the two arms of intervention.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: One hundred and sixteen (116) participants will be randomized in a 1:1 ratio, to either one of the two arms of this trial. This study will consist of 2 time periods/4 visits 1. Screening 2. Day 1 (Treatment start day, 7 days after visit 0) 3. Day 14 ± 3 days (Treatment end day) 4. Day 28 ± 3 days (Treatment drug-free follow-up end day)

Study Record Dates

• First Submitted: June 19, 2019
• First Posted: December 3, 2019
• Study Start: November 22, 2023
• Primary Completion: May 22, 2024
• Study Completion: November 22, 2024
• Last Updated: March 12, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CO (1)