Clinical trial NCT00661141: Phase IIa Study of Fomepizole for Acetaldehyde Toxicity After Ethanol Exposure in Subjects With Altered Ethanol Metabolism
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aldehyde Dehydrogenase-2 (ALDH2) Deficiency
Keywords: acetaldehyde
ethanol
ALDH2
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2008-04-18
Enrollment: 32
Sex: ALL
Minimum age (years): 21
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Study with completed results acquired from Horizon in 2024.

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

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs), Serious AEs, and AEs Leading to Study Discontinuation
timeFrame: Study Day 0 through Study Visit Day 7
Secondary outcomes:
measure: Pharmacokinetics (PK) of 4-MP: Maximum Plasma Concentration (Cmax)
timeFrame: 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
measure: PK of 4-MP: Dose-Normalized (DN) Cmax
timeFrame: 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
measure: PK of 4-MP: Time to Cmax (Tmax)
timeFrame: 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
measure: PK of 4-MP: Area Under the Plasma Concentration-Time Curve (AUC), Calculated to the Last Measured Concentration (AUC[0-t])
timeFrame: 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
measure: PK of 4-MP: DN AUC(0-t)
timeFrame: 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
measure: PK of 4-MP: AUC, From Time 0 Extrapolated to Infinite Time (AUC[0-∞])
timeFrame: 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
measure: PK of 4-MP: DN AUC(0-∞)
timeFrame: 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
measure: PK of 4-MP: Percentage of AUC0-∞ Obtained by Extrapolation (AUC%Extrap)
timeFrame: 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
measure: PK of 4-MP: Half-Life (T1/2)
timeFrame: 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
measure: PK of 4-MP: Apparent Clearance (CL/F)
timeFrame: 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
measure: PK of 4-MP: Apparent Volume of Distribution During Terminal Phase (Vz/F)
timeFrame: 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
measure: PK of Ethanol: Cmax
timeFrame: 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
measure: PK of Ethanol: DN Cmax
timeFrame: 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
measure: PK of Ethanol: Tmax
timeFrame: 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
measure: PK of Ethanol: AUC(0-t)
timeFrame: 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
measure: PK of Ethanol: DN AUC(0-t)
timeFrame: 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
measure: PK of Ethanol: AUC(0-∞)
timeFrame: 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
measure: PK of Ethanol: DN AUC(0-∞)
timeFrame: 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
measure: PK of Ethanol: AUC%Extrap
timeFrame: 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
measure: PK of Ethanol: T1/2
timeFrame: 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
measure: PK of Ethanol: CL/F
timeFrame: 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
measure: PK of Ethanol: Vz/F
timeFrame: 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
measure: PK of Acetaldehyde: Cmax
timeFrame: 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
measure: PK of Acetaldehyde: DN Cmax
timeFrame: 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
measure: PK of Acetaldehyde: Tmax
timeFrame: 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
measure: PK of Acetaldehyde: AUC(0-t)
timeFrame: 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
measure: PK of Acetaldehyde: DN AUC(0-t)
timeFrame: 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
measure: PK of Acetaldehyde: AUC(0-∞)
timeFrame: 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
measure: PK of Acetaldehyde: DN AUC(0-∞)
timeFrame: 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
measure: PK of Acetaldehyde: AUC%Extrap
timeFrame: 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
measure: PK of Acetaldehyde: T1/2
timeFrame: 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
Other outcomes:
Locations:
city: Honolulu
country: United States
facility: Covance Honolulu CRU
state: Hawaii
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Inoue K, Fukunaga M, Kiriyama T, Komura S. Accumulation of acetaldehyde in alcohol-sensitive Japanese: relation to ethanol and acetaldehyde oxidizing capacity. Alcohol Clin Exp Res. 1984 May-Jun;8(3):319-22. doi: 10.1111/j.1530-0277.1984.tb05519.x.
citation: Inoue K, Kera Y, Kiriyama T, Komura S. Suppression of acetaldehyde accumulation by 4-methylpyrazole in alcohol-hypersensitive Japanese. Jpn J Pharmacol. 1985 May;38(1):43-8. doi: 10.1254/jjp.38.43.
citation: Tardif R, Liu L, Raizenne M. Exhaled ethanol and acetaldehyde in human subjects exposed to low levels of ethanol. Inhal Toxicol. 2004 Apr;16(4):203-7. doi: 10.1080/08958370490277272.
citation: Yokoyama T, Yokoyama A, Kato H, Tsujinaka T, Muto M, Omori T, Haneda T, Kumagai Y, Igaki H, Yokoyama M, Watanabe H, Yoshimizu H. Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men. Cancer Epidemiol Biomarkers Prev. 2003 Nov;12(11 Pt 1):1227-33.