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

• Status: Completed
• Trial end date: 2008-06-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Horizon Pharma USA, Inc.; Raptor Pharmaceuticals Inc.
• Collaborator: Ted Daley, President
• Treatments: Ethanol; Fomepizole

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