Acetaminophen ToxicityPhase 4APAPIINCT02322879
Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing
A Phase 4 study testing First Treatment Period, Washout and Second Treatment Period in people with Acetaminophen Toxicity, run by Beth Israel Deaconess Medical Center at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 20 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Acetaminophen Toxicity
- What is being tested?
- First Treatment Period, Washout and Second Treatment Period
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- May 2013to Dec 2016
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy volunteers ages 20-40
- Patients not taking any chronic medications
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
About this study
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.
Read the 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
- Being tested
- First Treatment Period, Washout, Second Treatment Period
- Keywords
- Acetaminophen, Propylene glycol
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
First Treatment PeriodDrug
(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)
WashoutOther
(duration: 14 days) At the end of the First intervention period all participants will enter a washout period.
Second Treatment PeriodDrug
(duration: 14 days) At the end of the washout period, participants will receive the alternative intervention.
| Study group | Role | What they receive |
|---|---|---|
| Acetaminophen first, then Acetaminophen + Propylene Glycol | Experimental | 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. Receives: Drug: First Treatment Period; Other: Washout; Drug: Second Treatment Period |
| Acetaminophen + Propylene Glycol first, then Acetaminophen | Experimental | 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. Receives: Drug: First Treatment Period; Other: Washout; Drug: Second Treatment Period |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: Daily during the treatment periods (D1-D14 and D29 to 42)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Dec 2014 (estimated)
- Study startMay 2013
- Primary completionAug 2016
- Study completionDec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acetaminophen ToxicityStudies of the same condition, open and under way.
- More trials run by Beth Israel Deaconess Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- 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 blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Beth Israel Deaconess Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Harvard University
- Responsible party
- Principal investigator, Michael Ganetsky, Beth Israel Deaconess Medical Center
- Investigators
- Steven Salhanick, MD, Principal investigator, Beth Israel Deaconess Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02322879
- Sponsor's protocol ID
- 2013P000070
- Acronym
- APAPII
- Status last verified
- Aug 2017
- First submitted
- 22 Oct 2014
- Last updated
- 1 Sep 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: We plan to publish the data in near future but there is no plan on sharing the individual participant data
Study at a glance
From the registry record, last updated by the sponsor on 1 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing
- ClinicalTrials.gov ID
- NCT02322879
- Acronym / sponsor ID
- APAPII / 2013P000070
- Conditions
- Acetaminophen Toxicity
- Keywords
- Acetaminophen, Propylene glycol
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Beth Israel Deaconess Medical CenterUniversity, hospital or other
- Collaborators
- Harvard University
- Study start
- May 2013
- Primary completion
- Aug 2016 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 23 Dec 2014 (estimated)
- Results
- Posted 1 Sep 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Acetaminophen first, then Acetaminophen + Propylene Glycol | Experimental | Drug: First Treatment Period, Other: Washout, Drug: Second Treatment PeriodSubjects 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. |
| Acetaminophen + Propylene Glycol first, then Acetaminophen | Experimental | Drug: First Treatment Period, Other: Washout, Drug: Second Treatment PeriodSubjects 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. |
Who may qualify
- Ages
- 20 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Healthy volunteers ages 20-40
- Patients not taking any chronic medications
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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) | Drug | Acetaminophen + Propylene Glycol first, then Acetaminophen, Acetaminophen first, then Acetaminophen + Propylene Glycol |
| Washout(duration: 14 days) At the end of the First intervention period all participants will enter a washout period. | Other | Acetaminophen + Propylene Glycol first, then Acetaminophen, Acetaminophen first, then Acetaminophen + Propylene Glycol |
| Second Treatment Period(duration: 14 days) At the end of the washout period, participants will receive the alternative intervention. | Drug | Acetaminophen + Propylene Glycol first, then Acetaminophen, Acetaminophen first, then Acetaminophen + Propylene Glycol |
Primary outcome
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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Sep 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. We plan to publish the data in near future but there is no plan on sharing the individual participant data
Related trials for Acetaminophen Toxicity
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Steven Salhanick, MD principal investigator
Beth Israel Deaconess Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing First Treatment Period, Washout and Second Treatment Period in people with Acetaminophen Toxicity, run by Beth Israel Deaconess Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 1 Sep 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rise in Plasma Transaminases: Proportion of Responders. (time frame: Daily during the treatment periods (D1-D14 and D29 to 42)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2017.