Hepatitis
Conditions
Keywords
Paracetamol, Acetaminophen, Acute liver failure, N-acetylcysteine, Acetaminophen overdose
Brief summary
To evaluate the efficacy and safety of TYNADOTE® in the treatment of acetaminophen overdose
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.
Interventions
DRUGTYNADOTE
Subjects will take 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses
DRUGPlacebo Oral Tablet
Subjects will take 200 mg/every 4 hours, with a loading dose (400 mg) and then followed by 17 maintenance doses
Sponsors
Taipei Veterans General Hospital, Taiwan
Sinew Pharma Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
placebo
Intervention model description
test drug
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alanine aminotransferase | Day 3 | Percentage change from baseline of ALT at Day 3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total bilirubin | Day 3, Day 7 and Day 21 | Incidence of total bilirubin \> 2.5mg/dL at Day 3, Day 7, Day 21 |
| Inte- rnational Normalize Ratio | Day 3, Day 7 and Day 21 | Incidence of INR \> 1.25 at Day 3, Day 7, Day 21 |
| Aspartate aminotransferase or Alanine aminotransferase | Day 3, Day 7 and Day 21 | Incidence of AST or ALT \>1000 U/L at Day 3, Day 7, Day 21 |
| Alanine aminotransferase | Day 7 | Percentage change from baseline of ALT at Day 7 |
| Mortality rate | Day 7 and Day 21 | Mortality rate at Day 7, Day 21 |
| Free plasma acetaminophen-cysteine (AAP-Cys) and AAP-Cys adducts | Day 1-3 | 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 |
| TYNADOTE® plasma concentration | Day 1-3 | The time-interval weighted area under the curve (AUC) of TYNADOTE® plasma concentration during 72-hour treatment period |
| Hepatic failure rate (hepatic encephalopathy, ascites, total bilirubin, INR or liver transplantation) | Day 7 and Day 21 | Hepatic failure rate (hepatic encephalopathy, ascites, total bilirubin \>2.5mg/dL, INR \>1.25, or liver transplantation) at Day 7, Day 21 |
Countries
Taiwan
Contacts
Primary ContactChengHuei Mr. Hsiong, Vice President
Backup ContactWanLing Ms. Yang, Research
Outcome results
None listed