Clinical trial NCT03451487: A Randomized, Single-blind, Parallel Group and Multiple - Dose Design Study
Official title: A Randomized, Single-blind, Parallel Group and Multiple - Dose Design Study to Evaluate the Pharmacokinetics of Acetaminophen and Its Toxic Metabolites With Panadol® and Various Formulations of SafeTynadol® in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acetaminophen Toxicity
Keywords: acetaminophen
acute liver failure
Lead sponsor: Sinew Pharma Inc.
Sponsor class: INDUSTRY
First posted: 2018-03-01
Enrollment: 28
Sex: ALL
Minimum age (years): 20
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single Blindie
Primary purpose: OTHER

Brief summary: To investigate and compare the possible response of Panadol® and SafeTynadol® formulations in healthy volunteers.

Detailed description: Acetaminophen (AAP) is the most popular used analgesic/ antipyretic drug with serious hepatotoxic adverse effects; suicidal or unintentional overdose of AAP-induced hepatotoxicity. Cytochrome P450 2E1 (CYP2E1) is thought contribute to the responsible reactive metabolite N-acetyl-p-benzoquinone (NAPQI) of AAP overdose-induced hepatotoxicity. Pharmaceutical excipients are inactive ingredients that are added to a pharmaceutical compound. The objective of this study was to investigate the possible response of Panadol® (AAP alone) and SafeTynadol® (AAP with various selected excipients combination) formulations, while observing the AAP toxic metabolites (AAP-Cys) circumstances change in healthy volunteers. According to the current safety data, could be potentially develop hepatotoxicity-free AAP new formulation drug.

Eligibility criteria: Inclusion Criteria:

1. Normal healthy adult subjects between 20-50 years of age.
2. Body weight within 80-120% of ideal body weight. Male: Ideal body weight = (height - 80) \* 0.7 Female: Ideal body weight = (height - 70) \* 0.6
3. Acceptable medical history and physical examination including:

   * normal ECG results within six months prior to Period I (or Period III or Period V) dosing.
   * no particular clinical significance in general disease history within two months prior to Period I (or Period III or Period V) dosing.
4. Acceptable clinical laboratory determinations without significant deviation from normal values within two months prior to Period I (or Period III or Period V) dosing, which includes AST (SGOT), ALT (SGPT), r-GT, alkaline phosphatase, total bilirubin, albumin, glucose, BUN, uric acid, creatinine, total cholesterol, triglyceride (TG) and oral galactose single point (OGSP).
5. Acceptable hematology within two months prior to the study, which includes hemoglobin, hematocrit, red blood cells, MCV, MCH, MCHC, white blood cells, differential white blood cells and platelets.
6. Acceptable urinalysis within two months prior to the study, which includes pH, blood, glucose and protein.
7. Signed the written informed consent to participate in this study.

Exclusion Criteria:

1. History or presence of alcohol abuse, defined as consumption of more than 210 mL of alcohol per week (the equivalent of 14 glasses of 120-mL wine or 14 cans of 350-mL beer), or other substance abuse within the prior two years.
2. A clinically significant disorder involving the allergy, cardiovascular, respiratory, renal, gastrointestinal/hepatic, immunologic, hematologic, endocrine or neurologic system(s) or psychiatric disease (as determined by the clinical investigator).
3. History of allergic response(s) to acetaminophen, mannitol, sucralose or related drugs.
4. History of clinically significant allergies including drug allergies or allergic bronchial asthma.
5. Evidence of chronic or acute infectious diseases.
6. Any clinically significant illness or surgery during the one month prior to Period I (or Period III or Period V) dosing (as determined by the clinical investigator).
7. Taking any drug known to induce or inhibit hepatic drug metabolism within one month prior to the beginning of the study.
8. Receiving any investigational drug within one month prior to Period I (or Period III or Period V) dosing.
9. Taking any prescription medication or any nonprescription medication within two weeks prior to Period I (or Period III or Period V) doing.
10. Donating greater than 150 ml of blood within two months prior to Period I (or Period III or Period V) dosing or donating plasma (e.g. plasmapheresis) within two weeks prior to Period I (or Period III or Period V) dosing.
11. Consumption of caffeine, xanthine-containing products (i.e. coffee, tea, caffeine-containing sodas, colas and chocolate, etc.) and/or alcohol within 48 hours prior to days on which dosing is scheduled and during the periods when blood samples are being collected.
12. Any other medical reason as determined by the clinical investigator.
13. Subject is pregnant or breastfeeding.
14. Women of childbearing potential disagree to use an acceptable method of contraception (e.g., hormonal contraceptives, IUD, barrier device or abstinence) throughout the study.

Primary outcomes:
measure: Percentage change from baseline of ALT peak level within study periods
timeFrame: Blood samples were collected on days 2-7 (before dosing)
Secondary outcomes:
measure: - Incidence of peak ALT elevations > 1X ULN within study periods;
timeFrame: Day 1-7
measure: - Incidence of peak ALT elevations > 2X ULN within study periods;
timeFrame: Day 1-7
measure: - Incidence of peak ALT elevations > 3X ULN within study periods;
timeFrame: Day 1-7
measure: - Incidence of peak ALT elevations > 5X ULN within study periods;
timeFrame: Day 1-7
measure: - Incidence of peak ALT elevations > 8X ULN within study periods;
timeFrame: Day 1-7
measure: - Incidence of total bilirubin ≥ 2.5mg/dL within study periods;
timeFrame: Day 1-7
measure: - Hepatic failure rate (hepatic encephalopathy, ascites, total bilirubin ≥ 2.5mg/dL or liver transplantation) within study periods;
timeFrame: Day 1-7
measure: - The time-interval weighted area under the curve (AUC) of free plasma acetaminophen-cysteine (AAP-Cys) and AAP-Cys adducts within study periods.
timeFrame: Day 1-7
measure: - The time-interval weighted area under the curve (AUC) of ALT level within study periods
timeFrame: Day 1-7
Other outcomes:
measure: - Incidence of adverse events
timeFrame: Day 1-12
measure: - Clinical laboratory test
timeFrame: Day 1-12
measure: - Clinical laboratory test
timeFrame: Day 1-12
measure: - Clinical laboratory test
timeFrame: Day 1-12
measure: - Clinical laboratory test
timeFrame: Day 1-12
measure: - Clinical laboratory test
timeFrame: Day 1-12
measure: - Clinical laboratory test
timeFrame: Day 1-12
measure: - Vital sign
timeFrame: Day 1-12
measure: - Vital sign
timeFrame: Day 1-12
measure: - Vital sign
timeFrame: Day 1-12
Locations:
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
state: Neihu District
Study officials:
affiliation: Principal Investigator
name: TeYu Mr Lin, Dr.
role: PRINCIPAL_INVESTIGATOR
References: