Phase 2 Study of NBMI Treatment in Patients With Mercury Toxicity (NBMI-Hg-COL)
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|ClinicalTrials.gov Identifier: NCT04183595|
Recruitment Status : Not yet recruiting
First Posted : December 3, 2019
Last Update Posted : December 3, 2019
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 400mg / 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 Atlántico, Colombia.
|Condition or disease||Intervention/treatment||Phase|
|Mercury Poisoning||Drug: (N1, N3-bis(2- mercaptoethyl)isophthalamide) Other: Excipients microcrystalline cellulose, silica and magnesium stearate||Phase 2 Phase 3|
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 Puerto Colombia,
Atlántico, and department of Atlántico:
One hundred and sixteen patients (116) will be randomized in a 1:1 ratio, to either one of the two arms of this trial:
This study will consist of 5 Phases / 5 Visits
- Treatment Period A
- Washout Period / Follow-Up Period A
- Treatment Period B
- Follow-Up Period B.
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 56 of the study.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||116 participants|
|Intervention Model:||Crossover Assignment|
|Intervention 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 5 Phases / 5 Visits
Once Period A is completed, there will be a 2 Weeks Washout Period and the patients will switch arms following a crossover approach.
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
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.
|Official Title:||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 Atlántico, Colombia|
|Estimated Study Start Date :||February 1, 2020|
|Estimated Primary Completion Date :||October 1, 2020|
|Estimated Study Completion Date :||October 1, 2020|
Experimental: Arm A: NBMI (Study Medication)
400mg / day N1, N3-BIS- (2-MERCAPTOETHYL) ISOPHTHALAMIDE (NBMI) treatment for 14 days, administered as two capsules of 100 mg of NBMI every 12 hours.
Drug: (N1, N3-bis(2- mercaptoethyl)isophthalamide)
400mg / day NBMI treatment for 14 days, administered as two capsules of 100 mg of NBMI every 12 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 # 3, research subjects will be asked to return the packaging with the remaining capsules or not, in order to estimate adherence to treatment.
The cross-treatment will be assigned using the same procedure.
Other Name: NBMI
Placebo Comparator: Arm B: Placebo
((Excipients microcrystalline cellulose, silica and magnesium stearate)) capsules will be administered every 12 hours for 14 days.
Other: Excipients microcrystalline cellulose, silica and magnesium stearate
Capsules will be administered every 12 hours for 14 days.
Other Name: Placebo
- Measure the "Change in the subject's urine mercury levels" [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]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
- Measure the "Change in the subject's blood iron levels" [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]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.
- Measure the "Change in the subject's blood glucose levels" [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]To measure efficacy, the evaluation of the difference in blood glucose levels, as percentage of glucose concentration, will be determined.
- Measure the "Change in the subject's renal function" [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]The difference in scores derived from the CKD-EPI Equation will be evaluated.
- Measure the "Frequency and Severity of Adverse Events" [ Time Frame: From the first dose of study medication until the Day 56 visit. ]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.
- Measure subject's "Variations in Mental Response ". [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]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.
- Measure subject's "Variations in General Clinical examination". [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]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).
- Measure subject's "Variations in Height". [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]As part of general physical examination variations in participants height will be measured in centimeters comparing measurements in the three visits.
- Measure subject's "Variations in Weight". [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]As part of general physical examination variations in participants weight will be measured in kilograms comparing measurements in the three visits.
- Mercury intoxication measured by Medical Intoxication Score [ Time Frame: Baseline (Before) treatment, Fourteen (14) days after the start of treatment, Fourteen (14) days after the end of treatment ]
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.
- Amalgam [ Time Frame: Baseline (Before) treatment ]Presence of amalgam through digital photos
- Diet [ Time Frame: The patients will keep a food diary during the study (days 1-56). ]During the course of the protocol, all patients will be given a patient's food diary, in which data like type and amount of food intake is self-reported by participants.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04183595
|Contact: Haley E Boyd, PhD||+1-859-266-92 00 (01)||firstname.lastname@example.org|
|Principal Investigator:||Andres Cadena-Bonfanti, MD MS Esp||Clinica de la Costa - Barranquilla, Colombia|