Overview
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.
Description
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.
Eligibility
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.