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

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ClinicalTrials.gov Identifier: NCT02322879
Recruitment Status : Completed
First Posted : December 23, 2014
Results First Posted : September 1, 2017
Last Update Posted : September 1, 2017
Sponsor:
Collaborator:
Harvard University
Information provided by (Responsible Party):
Michael Ganetsky, Beth Israel Deaconess Medical Center

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.

Condition or disease Intervention/treatment Phase
Acetaminophen Toxicity Drug: First Treatment Period Other: Washout Drug: Second Treatment Period Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Eligible subjects will then be randomized at a 1:1 ratio to receive either acetaminophen (APAP) or APAP + propylene glycol for 2 weeks (Treatment Period 1). At the end of the Treatment Period 1 subjects will enter the Wash-Out period for 2 weeks. Study subjects will then receive the alternative treatment for 2 weeks (Treatment Period 2). Overall, the maximum duration of treatment is approximately 6 weeks.

RESPONDERS: Subjects whose transaminase levels rise to 3 times normal or greater during either of the Treatment Periods will be deemed responders and the intervention will cease.

  • If subjects are in the Treatment Period 1, they will enter the washout period and continue to return daily to ensure that liver function tests decline. After the 2 week washout-period, responders will cross over to Treatment Period 2.
  • If subjects are in the Treatment Period 2 phase, they will continue to return to the CRC and have their transaminases checked until they return to normal.
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing
Study Start Date : May 2013
Actual Primary Completion Date : August 2016
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Rise in Plasma Transaminases: Proportion of Responders. [ Time Frame: Daily during the treatment periods (D1-D14 and D29 to 42) ]
    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)



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Ages Eligible for Study:   20 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02322879


Locations
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United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Harvard University
Investigators
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Principal Investigator: Steven Salhanick, MD Beth Israel Deaconess Medical Center

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Responsible Party: Michael Ganetsky, Assistant Professor of Emergency Medicine, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT02322879     History of Changes
Other Study ID Numbers: 2013P000070
First Posted: December 23, 2014    Key Record Dates
Results First Posted: September 1, 2017
Last Update Posted: September 1, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: We plan to publish the data in near future but there is no plan on sharing the individual participant data

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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
Keywords provided by Michael Ganetsky, Beth Israel Deaconess Medical Center:
Acetaminophen
Propylene glycol
Additional relevant MeSH terms:
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Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics