To Evaluate the Efficacy and Safety of TYNADOTE® in the Treatment of Acetaminophen Overdose

Hepatitis Clinical Trial

Official title:

An Exploratory Study to Evaluate the Efficacy and Safety of TYNADOTE® Combined N-acetylcysteine in the Treatment of Acetaminophen Overdose

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05557448
• Other study ID #: TYNADOTE-2-001
• Status: Recruiting
• Phase: Phase 2
• Start date: May 1, 2023
• Est. completion date: December 2026

Study information

• Verified date: January 2024
• Source: Sinew Pharma Inc.
• Contact: ChengHuei Mr. Hsiong, Vice President
• Phone: +886-2-2788-5365
• Email: info[@]sinewpharma.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the efficacy and safety of TYNADOTE® in the treatment of acetaminophen overdose

Description:

This will be a 21-day study to evaluate the efficacy and safety of TYNADOTE® in the treatment of acetaminophen overdose.

After the inform consent is obtained from the subject or his/her legal guardians, the designated assessment will be performed. Subjects who fulfill all the inclusion and exclusion criteria will be eligible to enter the study. Except standard NAC antidote therapy, subjects would be randomized as 1:1 ratio to combine oral TYNADOTE® or placebo.

Eligible subjects will be randomized to receive oral TYNADOTE®/placebo combined iv NAC, and the regimen was listed as below:

The NAC intravenous loading dose is 150 mg/kg over a period of 15 to 60 minutes, followed by an infusion of 12.5 mg/kg per hour over a 4-hour period, and finally an infusion of 6.25 mg/kg per hour over a 16-hour period. Study drug, TYNADOTE® /placebo, should be given a loading dose of 400 mg, followed by 17 maintenance doses of 200 mg every 4 hours (Day 1 to Day 3).

During the treatment period, vital signs will be checked 15 minutes prior to dosing, 30 minutes, 60 minutes, then 2, 4, 8, 12, 24, 36, 48, 60 and 72 hours after first dosing. Blood samples will be collected for liver injuries and function test, including AST, ALT, total bilirubin, direct bilirubin and prothrombin time (INR), prior to dosing, 4 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours after first dosing. Blood samples for drug/metabolites concentration, including TYNADOTE® plasma concentration (trough level), plasma acetaminophen concentration, AAP-Cys and AAP-Cys adducts concentration, prior to dosing, 4 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours and 72 hours after first dosing. Blood samples for biochemistry and hematology, Day 1-3.

After completing the treatment (Day 3), subject will conduct the following evaluations before discharge:

• Review of adverse events

• Review of concomitant medications

• Physical examination On Day 7 and Day 21, subjects should return to the clinics for liver injuries/function follow up and reviewing the adverse events.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: December 2026
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

• Poisoning and hospitalized patients taking acetaminophen.

• Acute ingestion of more than 150 mg/kg or plasma concentration of Acetaminophen is above the treatment line on single acute acetaminophen overdose nomogram.

• Male or female with age more than 20 years at Screening.

• Ability and willingness to provide informed consent, adhere to the study visit schedule and complete all study assessments.

Exclusion Criteria:

• Subjects with Sequential Organ Failure Assessment (SOFA) Score higher than 12.

• Subjects who fulfilled the King's College Hospital (KCH) Criteria for liver transplantation.

• Subjects who was conscious disturbance.

• History of allergic response(s) to N-acetylcysteine (NAC), mannitol, sucralose or related drugs.

• Subject who was unable to take medicine by oral route.

• Receiving any investigational drug within 30 days prior to first dosing.

• Subject who had attacked asthma or bronchitis combined with medication therapy within six months prior to enrollment.

• Donating greater than 150 mL of blood within two months prior to first dosing or donating plasma (e.g. plasmapheresis) within 14 days prior to first dosing. All subjects will be advised not to donate blood for four weeks after completing the study.

• Subject is pregnant or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test at baseline.

• Anuria, pulmonary congestion, severe congestive heart failure, brain hemorrhage, or any conditions that in the opinion of the investigator may interfere with the evaluation of study objectives.

• The combination of poisoning contains acetaminophen and other compound.

• Body weight less than 50 kg.

Related Conditions & MeSH terms

• Drug Overdose
• Hepatitis

Intervention

Drug:
• TYNADOTE
Subjects will take 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses
• Placebo Oral Tablet
Subjects will take 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses

Locations

Country	Name	City	State
Taiwan	Taipei Veterans General Hospital	Taipei City	Beitou District

Sponsors (2)

Lead Sponsor	Collaborator
Sinew Pharma Inc.	Taipei Veterans General Hospital, Taiwan

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Alanine aminotransferase	Percentage change from baseline of ALT at Day 3.	Day 3
Secondary	Alanine aminotransferase	Percentage change from baseline of ALT at Day 7	Day 7
Secondary	Alanine aminotransferase	Percentage change from baseline of AST at Day 3, Day 7	Day 7
Secondary	Total bilirubin	Incidence of total bilirubin > 2.5mg/dL at Day 3, Day 7, Day 21	Day 3, Day 7 and Day 21
Secondary	Inte- rnational Normalize Ratio	Incidence of INR > 1.25 at Day 3, Day 7, Day 21	Day 3, Day 7 and Day 21
Secondary	Aspartate aminotransferase or Alanine aminotransferase	Incidence of AST or ALT >1000 U/L at Day 3, Day 7, Day 21	Day 3, Day 7 and Day 21
Secondary	Hepatic failure rate (hepatic encephalopathy, ascites, total bilirubin, INR or liver transplantation)	Hepatic failure rate (hepatic encephalopathy, ascites, total bilirubin >2.5mg/dL, INR >1.25, or liver transplantation) at Day 7, Day 21	Day 7 and Day 21
Secondary	Mortality rate	Mortality rate at Day 7, Day 21	Day 7 and Day 21
Secondary	Free plasma acetaminophen-cysteine (AAP-Cys) and AAP-Cys adducts	The time-interval weighted area under the curve (AUC) of free plasma acetaminophen-cysteine (AAP-Cys) and AAP-Cys adducts within 72-hour treatment period	Day 1-3
Secondary	TYNADOTE® plasma concentration	The time-interval weighted area under the curve (AUC) of TYNADOTE® plasma concentration during 72-hour treatment period	Day 1-3