Safety, Tolerability, and Pharmacokinetic Study of Methylene Blue Following a 1 mg/kg Intravenous Dose in Healthy Adults

Study Overview
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Brief Summary
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A Phase 1 trial to assess the single-dose safety, tolerability, and pharmacokinetic (PK) of Methylene Blue Injection, USP 1 mg/kg in healthy adult voluneetrs.

Detailed Description
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This is an open-label, single-center, one-arm, safety, tolerability, and PK study in healthy male and female volunteers of Methylene Blue Injection, USP. Following an overnight fast, twelve healthy adult male and female volunteers will receive a single dose of study drug at a dose of 1 mg/kg solution per kg given intravenously over a period of 5 minutes followed by serial venous blood sampling at 0.042, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 16, 36, 48, and 72 hours postdose.

Official Title
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A One-Period, Single-Dose, Safety, Tolerability, and Pharmacokinetic Study of Methylene Blue Injection USP Following a 1 mg/kg Intravenous Dose in Healthy Adult Volunteers

Conditions
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Methemoglobinemia, Congenital Methemoglobinemia

Intervention / Treatment
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* Drug: Methylene Blue


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male or female volunteers, 18-60 years of age, inclusive. Weigh at least 52 kg for males and 45 kg for females and within the normal range according to accepted normal values of the Body Mass Index (BMI) chart 18.5-29.9 kg/m² inclusive. Medically healthy with no clinically significant laboratory profiles, vital signs, or ECG's; as deemed by the PI. For females of childbearing potential: either be sexually inactive (abstinent) for 14 days prior to the first dose and throughout the study or be using acceptable birth control methods. Female subjects who claim to be sexually inactive, but become sexually active during the course of the study must agree to use a barrier method (e.g. condom, diaphragm)with spermicide from the time of the start of sexual activity through at least 30 days following dosing. In addition, female subjects of childbearing potential will be advised to remain sexually inactive or to keep the same birth control method for at least 30 days following dosing. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to Day 1: Hysteroscopic tubal ligation (with a copy of the confirmation test) and be using a barrier method (condom or diaphragm) and spermicide throughout the study; Bilateral tubal ligation and be using a barrier method (condom or diaphragm) and spermicide throughout the study; Hysterectomy; Bilateral oophorectomy or be postmenopausal with amenorrhea for at least 1 year prior to Day 1 and follicle stimulating hormone (FSH) serum levels ≥ 40 mIU/mL. Females on hormone replacement therapy may be deemed eligible for participation in the study even if their FSH levels < 40 mIU/mL, if they are able to provide documentation of FSH levels 40 mIU/mL before initiation of hormone replacement therapy. Males must use condom with spermicide when engaged in sexual activity and must agree to refrain from sperm donation from check-in through 90 days postdose. Willing to answer inclusion and exclusion criteria questionnaire at check-in. Give voluntary written informed consent to participate in the study. Be able to comply with the protocol and the assessments therein. Exclusion Criteria: History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease in the opinion of the PI. History or presence of alcoholism within the past 2 years. History or presence of drug abuse within the past 2 years. History or presence of hypersensitivity or idiosyncratic reaction to Methylene Blue. History or presence of G6PD dehydrogenase deficiency, retinopathy, blood disorder, myasthenia gravis, psoriasis, epilepsy, clinically significant allergies (except for mild forms of hay fever), or any other clinically significant medical condition, which in the opinion of the PI, might interfere with study participation. History or laboratory evidence of renal insufficiency. Any screening laboratory test with clinically significant abnormalities in the opinion of the PI (including cell blood count, creatinine, or liver function tests). Have used any drug that acts as a seotonin reuptake inhibitor (SRIs) e.g. selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, or ergot alkaloids within 30 days (or 5 half-lives of the compound, whichever is longer) prior to study drug dosing. Female subjects who are pregnant or lactating, or female subjects who are likely to become pregnant during the study. Had positive results for the urine drug/alcohol screen at screening or check-in. Had positive results at screening for HIV, HBsAg, or HCV. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening. Heart rate is lower than 40 bpm or higher than 99 bpm at screening. QTc interval is >430 msec (males) or >450 msec (females) or deemed clinically abnormal by the PI or use of any drug or agent suspected of causing QT prolongation or torsade de pointes within 14 days (or 5 half- lives of the compound, whichever is longer) prior to study drug dosing. Have been on a special diet (for whatever reason) within the 28 days prior to study drug dosing, and throughout the study. Have made a donation of blood or had significant blood loss within 56 days prior to study drug dosing. Have made a plasma donation within 7 days prior to study drug dosing. Have received Methylene Blue within 72 hours prior to study drug dosing. Have participated in another clinical trial within 30 days (or 5 half-lives of the compound, whichever is longer) prior to study drug dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylene Blue Injection, USP<br>Single dose of Methylene Blue Injection, USP at a dose of 1 mg/kg solution per kg given intravenously over a period of approximately 5 minutes. | Drug: Methylene Blue<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the AUC0-t (ng*hr/mL) of Methylene Blue |  | 72 hours postdose | 
| Assess the AUC0- infinity (ng*hr/mL) of Methylene Blue |  | 72 hours postdose | 
| Assess the AUC%extrap (%) of Methylene Blue |  | 72 hours postdose | 
| Assess the AUCR (%) of Methylene Blue |  | 72 hours postdose | 
| Assess the CL (L/hr) of Methylene Blue |  | 72 hours postdose | 
| Assess the Cmax (ng/mL) of Methylene Blue |  | 72 hours postdose | 
| Assess the tmax (hr) of Methylene Blue |  | 72 hours postdose | 
| Assess the t½ (hr) of Methylene Blue |  | 72 hours postdose | 
| Asses the λz (1/hr) of Methylene Blue |  | 72 hours postdose | 
| Assess the Vz (L) of Methylene Blue |  | 72 hours postdose | 
| Assess the MRT (hr) of Methylene Blue |  | 72 hours postdose |