Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing (APAPII)

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.

Study Overview

• Status: Completed
• Conditions: Acetaminophen Toxicity
• Intervention / Treatment: Drug: First Treatment Period; Other: Washout; Drug: Second Treatment Period

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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); Other: Washout; (duration: 14 days) At the end of the First intervention period all participants will enter a washout period.; Drug: Second Treatment Period; (duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.
Experimental: 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.	Drug: 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); Other: Washout; (duration: 14 days) At the end of the First intervention period all participants will enter a washout period.; Drug: Second Treatment Period; (duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rise in Plasma Transaminases: Proportion of Responders.	Blood tests to monitor Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) were obtained on every visit prior dosing. ALT and AST were analyzed on a Roche Cobas c501 chemistry module at BIDMC. Responders was defined as peak ALT increased 2x baseline (average of first 3 days)	Daily during the treatment periods (D1-D14 and D29 to 42)

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Harvard University
• Investigators: Principal Investigator: Steven Salhanick, MD, Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: October 22, 2014
• First Submitted That Met QC Criteria: December 22, 2014
• First Posted (Estimate): December 23, 2014

Study Record Updates

• Last Update Posted (Actual): September 1, 2017
• Last Update Submitted That Met QC Criteria: August 2, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Acetaminophen; Propylene glycol
• Other Study ID Numbers: 2013P000070

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: We plan to publish the data in near future but there is no plan on sharing the individual participant data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No