Phase IIa Study of Fomepizole for Acetaldehyde Toxicity After Ethanol Exposure in Subjects With Altered Ethanol Metabolism
Information source: Raptor Pharmaceuticals Inc.
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Acetaldehyde Toxicity; ALDH2 Deficiency; Altered Ethanol Metabolism
Intervention: fomepizole; (Drug)
Phase: Phase 1/Phase 2
Sponsored by: Raptor Pharmaceuticals Inc.
Official(s) and/or principal investigator(s):
James Ruckle, MD, Principal Investigator, Affiliation: Covanance Honolulu CRU
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.
Official title: Phase IIa, Prospective, Randomized, Blinded, Intra-Subject Controlled, Dose Escalation Study of Fomepizole for Mitigation of Acetaldehyde Related Toxicity in Human Subjects With Altered Ethanol Metabolism With Concomitant Ethanol Exposure
Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Primary outcome: Safety and tolerability of oral fomepizole with concomitant ethanol administration in subjects with symptoms of with symptoms of acetaldehyde toxicity associated with altered ethanol metabolism
Secondary outcome: PK of 4-MP, ethanol and acetaldehyde in subjects with symptoms of acetaldehyde toxicity associated with altered ethanol metabolism following a single oral dose of fomepizole with concomitant ethanol administration
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.
Minimum age: 21 Years.
Maximum age: 50 Years.
- Signed informed consent
- Age 21 to 50 years
- Subject of Japanese descent
- History of flushing, with or without palpitations, or nausea (ALST ≥ 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)
- 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
- 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
- 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
- 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
- Known hypersensitivity reaction to Antizol® or other pyrazoles, tomato juice
- Abnormal laboratory results, including:
- WBC ≤3. 5 × 109/L or neutrophil count ≤2. 0 × 109/L
- Hemoglobin <12. 0 or >16. 0 gm/dL
- Creatinine ≥2 mg/dL
- Total bilirubin ≥2 mg/dL
- Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥2 times
the upper limit of normal (ULN)
- PaO2 ≤95% on room air by pulse oximetry
- Urine dipstick positive for protein, blood, ketones, glucose or leukocyte
- 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
- 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
Locations and Contacts
Covance Honolulu CRU, Honolulu, California 96813, United States
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Starting date: April 2008
Last updated: September 25, 2012