Phase IIa Study of Fomepizole for Acetaldehyde Toxicity After Ethanol Exposure in Subjects With Altered Ethanol Metabolism

Study Overview
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Brief Summary
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This trial will evaluate if fomepizole (4-methylpyrazole) can treat symptoms associated with alcohol intolerance due to aldehyde dehydrogenase 2 (ALDH2) deficiency, an inherited metabolic disorder. These symptoms include flushing, nausea, headache, shortness of breath and dizziness, resulting from exposure to acetaldehyde, the primary metabolite of ethanol. Long-term, serious health risks have been associated with repeated exposure to acetaldehyde, a carcinogen, among ALDH2-deficient individuals.

Detailed Description
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Approximately 32 subjects will be enrolled in ascending dosing cohorts of 8 subjects each. Each subject will receive an oral dose of study drug (fomepizole or placebo) with concomitant ethanol with group assignment in a randomized 1:1:1:1 ratio (2 subjects each group) on Study Day 1. Each subject is their own intra-subject control with the alternative study drug (fomepizole or placebo) administered on the next day (Study Day 2). Four subjects in each cohort will receive study drug (fomepizole or placebo) administered 30 minutes prior to ethanol, 4 with study drug (fomepizole or placebo) administered 30 minutes after ethanol. The study will assess safety and tolerability of fomepizole and the PK/PD of 4-MP, ethanol and acetaldehyde in the subject population.

Official Title
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A Phase IIa, Prospective, Randomized, Blinded, Intra-Subject Controlled, Single Dose, Dose Escalation Study of Antizol® for Mitigation of Acetaldehyde Related Toxicity in Human Subjects With Symptoms of Inborn Altered Ethanol Metabolism With Concomitant Ethanol Exposure

Conditions
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Aldehyde Dehydrogenase-2 (ALDH2) Deficiency

Intervention / Treatment
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* Drug: Antizol
* Drug: Placebo
* Other: Ethanol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Age 21 to 50 years Subject of Japanese descent History of flushing, with or without palpitations, or nausea (Alcohol Sensitivity Screening Test ≥ 3.1) following occasional or inadvertent ethanol consumption either currently or in the past Subjects must be healthy volunteers with no other clinically relevant abnormalities as determined by medical history, blood chemistry, complete blood count (CBC), urinalysis,and 12-lead electrocardiogram (ECG) Positive skin ethanol patch test (100 μL of 70% ethanol on a lint pad applied to skin for 7 minutes results in an area of erythema) For Cohort 4, enrolled subjects were either homozygous or heterozygous for the ALDH2*2 genotype as assessed by genotyping at Screening Exclusion Criteria: Vaccination within 2 weeks of Day 1 Current respiratory disease or a past history of chronic respiratory disease, or current smoker within last six months Any one of the following Screening ECG findings: QTc (Bazett) interval duration greater than 450 msec (male) or 470 msec (female), or QRS interval greater than 120 msec, or PR interval greater than 220 msec History or evidence of drug or alcohol abuse or regular consumption of more than 8 units of alcohol daily (1 unit = 300 mL beer, 1 glass wine, 1 measure spirit) or those who may have difficulty abstaining from non study alcohol during the 36 hours prior to dose administration and until completion of blood sampling on Day 7 Subjects who have donated blood totalling more than 550 mL within the 3 months prior to Day 1 Use of any prescription medication other than oral contraceptives during the 14 days prior to Day 1, unless approved by both the Principal Investigator (PI) and the Sponsor Inability to abstain from smoking any tobacco product from within prior to 2 hours of blood sampling to after 2 hours of blood sampling during the study period. Use of any over-the-counter product, herbal product, diet aid, hormone supplement, etc., within 14 days prior to Day 1 unless approved by both the PI and the Sponsor Chronic use of pain medications Administration of an investigational agent within the last 30 days (or within a period of less than 5 times the agent's half-life, whichever is longer) prior to Day 1 Major surgery within 60 days prior to Day 1, or any planned surgery or medical procedure during the study period (through Day 7) Positive alcohol breath-test or Positive drug screen (e.g., opiates, barbiturates, cannabinoids, benzodiazepines, cocaine, amphetamines) during screening or at Day 0 Check-In Known hypersensitivity reaction to Antizol® or other pyrazoles, tomato juice Abnormal laboratory results, including: WBC ≤3.5 × 109/L or neutrophil count ≤2.0 × 10^9/L Hemoglobin <12.0 or >16.0 gm/dL Creatinine ≥2 mg/dL Total bilirubin ≥2 mg/dL Alanine aminotransferase and/or aspartate aminotransferase ≥2 times the upper limit of normal PaO2 ≤95% on room air by pulse oximetry Urine dipstick positive for protein, blood, ketones, glucose or leukocyte esterase Any other clinically significant abnormal result for hematology, clinical chemistry, or urinalysis at screening or check-In Positive serum pregnancy test for females of childbearing potential Subject and/or partner unable or unwilling to use an effective form of barrier contraceptives during the course of the study and for 7 days after study drug administration. Cancer (excluding adequately treated basal cell carcinoma) within the last 5 years Significant past medical history of hepatic, renal, cardiovascular (including family history of prolonged QT syndrome), pulmonary, gastrointestinal, hematological, locomotor, immunologic, ophthalmologic, metabolic endocrine or other diseases; or any condition that in the opinion of the Investigator would complicate or compromise the study, or the well-being of the subject Any other reason, which in the opinion of the Principal Investigator, would prevent the subject from completing or following the study schedule

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Antizol 1.0 mg/kg<br>Participants receive alternating study treatment (oral fomepizole 1.0 mg/kg or placebo) on 2 sequential days (Study Day 1 and Study Day 2), administered 30 minutes prior to ethanol or 30 minutes after ethanol. | Drug: Antizol<br> <br> * Other names: 4-MP;Drug: Placebo<br> <br> Other: Ethanol<br>* oral dose of ethanol (0.5 g/kg)<br>|
| Experimental: Cohort 2: Antizol 3.0 mg/kg<br>Participants receive alternating study treatment (oral fomepizole 3.0 mg/kg or placebo) on 2 sequential days (Study Day 1 and Study Day 2), administered 30 minutes prior to ethanol or 30 minutes after ethanol. | Drug: Antizol<br> <br> * Other names: 4-MP;Drug: Placebo<br> <br> Other: Ethanol<br>* oral dose of ethanol (0.5 g/kg)<br>|
| Experimental: Cohort 3: Antizol 5.0 mg/kg<br>Participants receive alternating study treatment (oral fomepizole 5.0 mg/kg or placebo) on 2 sequential days (Study Day 1 and Study Day 2), administered 30 minutes prior to ethanol. | Drug: Antizol<br> <br> * Other names: 4-MP;Drug: Placebo<br> <br> Other: Ethanol<br>* oral dose of ethanol (0.5 g/kg)<br>|
| Experimental: Cohort 4: Antizol 1.0 mg/kg<br>Participants receive alternating study treatment (oral fomepizole 7.0 mg/kg or placebo) on 2 sequential days (Study Day 1 and Study Day 2), administered 30 minutes prior to ethanol. | Drug: Antizol<br> <br> * Other names: 4-MP;Drug: Placebo<br> <br> Other: Ethanol<br>* oral dose of ethanol (0.5 g/kg)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious AEs, and AEs Leading to Study Discontinuation | AEs were collected to evaluate the safety and tolerability of oral Antizol with concomitant ethanol administration in particitpants with symptoms of acetaldehyde toxicity associated with altered ethanol metabolism. AE: any untoward medical event that occurs following the first administration of study medication until the study participant's last study visit, whether or not the event is considered drug related. SAE: an event that meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in the offspring of an exposed subject; is medically significant or an important medical event as assessed by investigator or sponsor; is, in the opinion of the investigator, an important medical event. | Study Day 0 through Study Visit Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of 4-MP: Maximum Plasma Concentration (Cmax) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: Dose-Normalized (DN) Cmax |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: Time to Cmax (Tmax) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: Area Under the Plasma Concentration-Time Curve (AUC), Calculated to the Last Measured Concentration (AUC[0-t]) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: DN AUC(0-t) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: AUC, From Time 0 Extrapolated to Infinite Time (AUC[0-∞]) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: DN AUC(0-∞) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: Percentage of AUC0-∞ Obtained by Extrapolation (AUC%Extrap) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: Half-Life (T1/2) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: Apparent Clearance (CL/F) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of 4-MP: Apparent Volume of Distribution During Terminal Phase (Vz/F) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: Cmax |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: DN Cmax |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: Tmax |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: AUC(0-t) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: DN AUC(0-t) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: AUC(0-∞) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: DN AUC(0-∞) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: AUC%Extrap |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: T1/2 |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: CL/F |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Ethanol: Vz/F |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: Cmax |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: DN Cmax |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: Tmax |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: AUC(0-t) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: DN AUC(0-t) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: AUC(0-∞) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: DN AUC(0-∞) |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: AUC%Extrap |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 
| PK of Acetaldehyde: T1/2 |  | Days 1 and 2: prior to administration of 1st treatment (ethanol or study drug); 10, 20, and 30 min prior to administration of second treatment (study drug or ethanol); 40, 50, 60 min and 2, 3, 4, 5, 6, and 8 hr post administration of 1st treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acetaldehyde, ethanol, ALDH2