NBMI Treatment in Patients With Mercury Toxicity

Study Overview
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Brief Summary
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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.

Detailed Description
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This is a Controlled Single-Center Double-Blind Crossover Clinical Trial Phase II b conducted in subjects with a history of chronic exposure to mercury in Colombia. One hundred and sixteen patients (116) will be randomized in a 1:1 ratio, to either one of the two arms of this trial: Group A: NBMI (study drug) with an oral dose of 600 mg corresponding to 6 capsules of 100 mg of NBMI every 24 hours for 14 days. Group B: Placebo 6 capsules, every 24 hours for 14 days. This study will consist of 2 time periods/4 visits Screening Day 1 (Treatment start day, 7 days after visit 0) Day 14 ± 3 days (Treatment end day) Day 28 ± 3 days (Treatment drug-free follow-up end day) After Screening a computer-generated scrambling code will be used for allocation in blocks of 4 to the two treatments. During enrollment, the proportion of subjects with or without a history of previous treatment by chelating will be monitored. The identity of patients included in the futility analysis will not be provided to the trial team, in order to preserve the blind aspect of the trial. The trial will be interrupted if the difference between the groups of treatment in the primary assessment is significantly (α = 0.05 unilateral) less than 10% in favor of any of the arms. A Data Monitoring Committee will be set up to monitor the safety and risk control general benefit. The committee's statistician and epidemiologist will carry out the evaluation. The identity of the research product associated with each randomization number will be kept hidden for the trial team and for the patients. The final analysis is planned for when 100% of the patients (116 patients) reach Day 28 of the study.

Official Title
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A Double-blinded, Randomized Controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of N1, N3-bis-(2-Mercaptoethyl) Isophthalamide (NBMI) in the Reduction of Mercury Levels, in Subjects Exposed to Mercury in Colombia

Conditions
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Mercury Poisoning

Intervention / Treatment
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* Drug: (N1, N3-bis(2- mercaptoethyl)isophthalamide)
* Other: Excipients microcrystalline cellulose, silica and magnesium stearate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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 Screening Day 1 (Treatment start day, 7 days after visit 0) Day 14 ± 3 days (Treatment end day) Day 28 ± 3 days (Treatment drug-free follow-up end day)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: NBMI (Study Medication)<br>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)<br>* 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.<br>* Other names: NBMI;|
| Placebo Comparator: Arm B: Placebo<br>(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<br>* 6 Capsules will be administered every 24 hours for 14 days.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure the Change in the subject's blood iron levels | To measure the efficacy, the evaluation of the difference in blood iron levels as the percentages of iron concentration, will be calculated. Immunoturbidimetry Test will be used as an indicator of iron reserves to determine serum ferritin (FS) 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 | To measure efficacy, the evaluation of the difference in blood glucose levels, as percentage of glucose concentration, will be determined. | 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 | The difference in scores derived from the CKD-EPI Equation will be evaluated. | 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 | Frequency and Severity of Adverse Events in the 14 day 400mg / day NBMI Treatment Group. Adverse Events will be encoded using the most recent version of the Medical Dictionary for Regulatory Activities. | From the first dose of study medication until the Day 56 visit. | 
| Measure subject's Variations in Mental Response . | The European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) to evaluate quality of life is an instrument to assess the state of health in multiple dimensions. The questionnaire has five questions with Likert (descriptive system) and an analog visual scale (EQ-VAS). The descriptive system defines health in terms of 5 dimensions: mobility, self-care, habitual activities, pain/discomfort and anxiety/Depression. Each dimension has 5 response categories: no problem, mild problems, moderate problems, serious problems and extreme problems. The EQ-VAS marked 0 (worst state of health) -100 (best state of health). The combination of the score in each dimension calculates an index value EQus which is equivalent to the QALY (quality-adjusted life year) value. Thus EQus= 1 is equivalent to QALY = 1, that means a year lived with perfect health, an EQus <1 is equivalent to a year lived with a lower level of health and EQus = 0 is equivalent to being dead. | Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment | 
| Measure subject's Variations in General Clinical examination. | A general physical examination of systems and organs will be conducted to determine whether there is or there is not a variation of health status (Yes/No scale). The organs and system that will be examined to determine a general health status are Head and Neck, Oral Cavity, Eyes, Ears, Nose, Cardiovascular System, Chest and Lungs, Abdomen, Skin, Lymphatic System, Neurological System, Renal System, Musculoskeletal System, Appearance). | Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment | 
| Measure subject's Variations in Height. | As part of general physical examination variations in participants height will be measured in centimeters comparing measurements in the three visits. | Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment | 
| Measure subject's Variations in Weight. | As part of general physical examination variations in participants weight will be measured in kilograms comparing measurements in the three visits. | Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment | 
| Mercury intoxication measured by Medical Intoxication Score | The medical intoxication score (MIS) is a tool created to identify mercury poisoning in patients. It is a score of ten points that is evaluated by a medical examination, neuromotor tests and an anamnestic questionnaire evaluating 8 elements: 1. Excessive salivation 2. Tremor during work 3. Problems sleeping at night 4. Bluish discoloration of the gums 5. Ataxic gait 6. Dysdiadocokinesia 7. Heel and chin test 8. Proteinuria. Each can have an assigned value of 0 or 1, specific to whether the symptom is absent (0) or present (1) or if the test result is negative (0) or positive (1). The medical score of mercury poisoning is the sum of the values of the elements. The worst case of worsening intoxication symptoms would be 10 and a healthy participant will get 0 score. Intoxication will be considered if score is 6 or greater than 6. | Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exposure to mercury, NBMI