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

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

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

Study Overview

• Status: Recruiting
• Conditions: Hepatitis
• Intervention / Treatment: Drug: TYNADOTE; Drug: Placebo Oral Tablet

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: ChengHuei Mr. Hsiong, Vice President; Phone Number: +886-2-2788-5365; Email: info@sinewpharma.com
• Study Contact Backup: Name: WanLing Ms. Yang, Research; Phone Number: +886-2-2788-5365; Email: wlyang@sinewpharma.com

Study Locations

• Taiwan
  • Beitou District
    • Taipei City, Beitou District, Taiwan, 11217
      • Recruiting
      • Taipei Veterans General Hospital
      • Contact: WanLing Ms Yang, Research; Phone Number: +886-2-2788-5365; Email: wlyang@sinewpharma.com
      • Contact: ChengHuei Mr Hsiong, Vice President; Phone Number: +886-2-2788-5365; Email: info@sinewpharma.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Test drug; 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses	Drug: TYNADOTE; Subjects will take 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses
Placebo Comparator: Placebo; 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses	Drug: Placebo Oral Tablet; Subjects will take 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alanine aminotransferase	Percentage change from baseline of ALT at Day 3.	Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alanine aminotransferase	Percentage change from baseline of ALT at Day 7	Day 7
Alanine aminotransferase	Percentage change from baseline of AST at Day 3, Day 7	Day 7
Total bilirubin	Incidence of total bilirubin > 2.5mg/dL at Day 3, Day 7, Day 21	Day 3, Day 7 and Day 21
Inte- rnational Normalize Ratio	Incidence of INR > 1.25 at Day 3, Day 7, Day 21	Day 3, Day 7 and Day 21
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
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
Mortality rate	Mortality rate at Day 7, Day 21	Day 7 and Day 21
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
TYNADOTE® plasma concentration	The time-interval weighted area under the curve (AUC) of TYNADOTE® plasma concentration during 72-hour treatment period	Day 1-3

Collaborators and Investigators

• Sponsor: Sinew Pharma Inc.
• Collaborators: Taipei Veterans General Hospital, Taiwan

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 22, 2022
• First Submitted That Met QC Criteria: September 27, 2022
• First Posted (Actual): September 28, 2022

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Acetaminophen; N-acetylcysteine; Paracetamol; Acute liver failure; Acetaminophen overdose
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Substance-Related Disorders; Drug Overdose
• Other Study ID Numbers: TYNADOTE-2-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No