Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

NCT ID: NCT02322879

Last Updated: 2017-09-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-31
• Study Completion Date: 2016-12-31

Brief Summary

A purpose of this protocol is to is to compare the metabolites of the toxic bioactivating pathway after acetaminophen alone or acetaminophen followed by Propylene Glycol (PG) and to determine if it prevents the formation of the toxic metabolites of acetaminophen.

Detailed Description

The purpose of this protocol is to contribute to our overarching purpose, which is to determine if inhibiting the bioactivation of acetaminophen (APAP) can prevent liver injury, and to further describe the initiating mechanisms of APAP induced liver injury. APAP induced liver injury is caused by metabolism and/or the resulting metabolites when APAP undergoes reductive metabolism via the cytochrome P450 (CYP) system, principally via CYP 2E1. Inhibition of CYP 2E1 activity protects against toxicity in rodents and tissue culture. Our prior research indicates that inhibition of CYP 2E1 by administering a pediatric preparation of APAP containing Propylene Glycol (PG), a known CYP 2E1 inhibitor, results in reduced production of CYP 2E1 derived metabolites via competitive inhibition.

In this proposed protocol the investigators will provide therapeutic doses of APAP and a separately administered non toxic dose of PG over a two-week period to healthy subjects. 20-75% of healthy people who take therapeutic doses of APAP for 7-28 days will have an asymptomatic and subclinical rise in transaminase levels that will return to baseline without adverse effect or therapy. 3 The return to baseline occurs despite continued dosing of APAP.

A primary purpose is to determine if PG is, in fact, the substance in the liquid preparation responsible for the effect the investigators observed in the investigators initial study. A secondary purpose is to obtain plasma samples for secondary metabolomic analysis to elucidate the effect of CYP 2E1 inhibition.

Specific Aims

• 1 To demonstrate that co-administration of PG with APAP prevents the rise in AST/ALT expected in approximately one third of subjects following therapeutic dosing of APAP over days.
• 2 To show that PG administered with APAP reduces toxic P450-derived metabolite production following therapeutic APAP administration.
• 3 To obtain plasma samples to undergo metabolomic and other analyses to determine the effects of CYP 2E1 inhibition in the setting of APAP administration.
• 4 To undergo metabolomic analyses on the day LFT's peak to determine differences in metabolomics parameters between subjects receiving propylene glycol plus acetaminophen versus just acetaminophen alone.

Conditions

Acetaminophen Toxicity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Acetaminophen first, then Acetaminophen + Propylene Glycol

Subjects in this arm will receive 4 grams of solid acetaminophen formulation for two weeks, followed by a two week wash out period.

Then, subjects will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks.

The total study time is 6 weeks.

Group Type: EXPERIMENTAL

First Treatment Period

Intervention Type: DRUG

(duration: 14 days) Subjects will be randomized to receive either of the 2 interventions (4 grams of solid acetaminophen formulation for two weeks vs. 4 grams of solid acetaminophen formulation + 70 mg/kg/day of liquid propylene glycol)

Washout

Intervention Type: OTHER

(duration: 14 days) At the end of the First intervention period all participants will enter a washout period.

Second Treatment Period

Intervention Type: DRUG

(duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.

Acetaminophen + Propylene Glycol first, then Acetaminophen

Subjects in this arm will receive 4 grams of solid acetaminophen formulation in addition to 70 mg/kg/day of liquid propylene glycol for two weeks, followed by a two week wash out period.

Then, subjects will receive 4 grams of solid acetaminophen formulation for two weeks.

The total study time is 6 weeks.

Group Type: EXPERIMENTAL

First Treatment Period

Intervention Type: DRUG

(duration: 14 days) Subjects will be randomized to receive either of the 2 interventions (4 grams of solid acetaminophen formulation for two weeks vs. 4 grams of solid acetaminophen formulation + 70 mg/kg/day of liquid propylene glycol)

Washout

Intervention Type: OTHER

(duration: 14 days) At the end of the First intervention period all participants will enter a washout period.

Second Treatment Period

Intervention Type: DRUG

(duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.

Interventions

First Treatment Period

(duration: 14 days) Subjects will be randomized to receive either of the 2 interventions (4 grams of solid acetaminophen formulation for two weeks vs. 4 grams of solid acetaminophen formulation + 70 mg/kg/day of liquid propylene glycol)

Intervention Type: DRUG

Washout

(duration: 14 days) At the end of the First intervention period all participants will enter a washout period.

Intervention Type: OTHER

Second Treatment Period

(duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Healthy volunteers ages 20-40
• Patients not taking any chronic medications

Exclusion Criteria

• Any history of liver disease
• Frequent alcohol use (2 or more drinks more than 4 times per week)
• Pregnant women
• Chronic medical condition requiring daily pharmacotherapy or the use of any daily prescription medications.
• Unable to provide informed consent

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Harvard University

OTHER

Sponsor Role: collaborator

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Michael Ganetsky

Assistant Professor of Emergency Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven Salhanick, MD

Role: PRINCIPAL_INVESTIGATOR

Beth Israel Deaconess Medical Center

Locations

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Countries

United States

Other Identifiers

2013P000070

Identifier Type: -

Identifier Source: org_study_id