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

NCT00661141 | Completed Phase 2 Results

• 1 other identifier: BP1-01-01
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

Aldehyde Dehydrogenase-2 (ALDH2) Deficiency

Keywords

acetaldehyde; ethanol; ALDH2

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (31)

• 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

Study Arms (4)

Cohort 1: Antizol 1.0 mg/kg

EXPERIMENTAL

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; Drug: Placebo; Other: Ethanol

Cohort 2: Antizol 3.0 mg/kg

EXPERIMENTAL

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; Drug: Placebo; Other: Ethanol

Cohort 3: Antizol 5.0 mg/kg

EXPERIMENTAL

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; Drug: Placebo; Other: Ethanol

Cohort 4: Antizol 1.0 mg/kg

EXPERIMENTAL

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; Drug: Placebo; Other: Ethanol

Interventions

Antizol DRUG

Also known as: fomepizole, 4-methylpyrazole, 4-MP

Cohort 1: Antizol 1.0 mg/kg; Cohort 2: Antizol 3.0 mg/kg; Cohort 3: Antizol 5.0 mg/kg; Cohort 4: Antizol 1.0 mg/kg

Placebo DRUG

Cohort 1: Antizol 1.0 mg/kg; Cohort 2: Antizol 3.0 mg/kg; Cohort 3: Antizol 5.0 mg/kg; Cohort 4: Antizol 1.0 mg/kg

Ethanol OTHER

oral dose of ethanol (0.5 g/kg)

Cohort 1: Antizol 1.0 mg/kg; Cohort 2: Antizol 3.0 mg/kg; Cohort 3: Antizol 5.0 mg/kg; Cohort 4: Antizol 1.0 mg/kg

Eligibility Criteria

• Age: 21 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Amgen: lead

Study Sites (1)

Covance Honolulu CRU

Honolulu, Hawaii, 96813, United States

Location

Related Publications (4)

• 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.

  PMID: 6377951 BACKGROUND

• 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.

  PMID: 4021229 BACKGROUND

• 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.

  PMID: 15204767 BACKGROUND

• 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.

  PMID: 14652286 BACKGROUND

MeSH Terms

Interventions

Fomepizole; 4-methylpiperazine-2,6-dione; Ethanol

Intervention Hierarchy (Ancestors)

Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Alcohols; Organic Chemicals

Results Point of Contact

• Title: Beth Robinson, Executive Director
• Organization: Horizon Pharma USA, Inc.

clinicaltrials@horizonpharma.com

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2008
• First Posted: April 18, 2008
• Study Start: April 1, 2008
• Primary Completion: June 1, 2008
• Study Completion: June 1, 2008
• Last Updated: December 27, 2024
• Results First Posted: September 15, 2017

Record last verified: 2024-12

Locations

US (1)