Phase IIa Study of Fomepizole for Acetaldehyde Toxicity After Ethanol Exposure in Subjects With Altered Ethanol Metabolism
Condition: Aldehyde Dehydrogenase-2 (ALDH2) Deficiency
Intervention: Antizol; Placebo; Ethanol
Intervention description: oral dose of ethanol (0.5 g/kg)
Intervention MeSH terms: Ethanol; Fomepizole
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 32.0
Sex: All
Minimum age: 21 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: acetaldehyde; ethanol; ALDH2

Summary:

      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.
    

Eligibility criteria:

        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