Clinical trial NCT04916795: A Study To Investigate The Pharmacokinetics, Pharmacodynamics, Safety And Tolerability Of Single Dose Vupanorsen In Healthy Chinese Adults
Official title: A PHASE 1, RANDOMIZED, OPEN-LABEL, SINGLE DOSE STUDY TO INVESTIGATE THE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF VUPANORSEN ADMINISTERED SUBCUTANEOUSLY TO HEALTHY CHINESE ADULTS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2021-06-08
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is a Phase 1, randomized, parallel-cohort, open-label study to characterize the pharmacokinetics, pharmacodynamics, safety and tolerability of vupanorsen following 80 mg and 160 mg single subcutaneous dose in healthy Chinese adults with elevated fasting triglyceride.


Eligibility criteria: Inclusion Criteria:

1. Male and female Chinese participants must be 18 to 65 years of age, inclusive, at the time of signing the ICD.

   * Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
   * Chinese participant is defined as individuals currently residing in mainland China who were born in China and have both parents of Chinese descent.
2. Male and female Chinese participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests (except for TG levels), and 12-lead ECG monitoring.
3. Fasting TG ≥ 90 mg/dL at Screening (up to 1 repeat allowed for TG and the second TG value will be used for the eligibility).
4. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
5. BMI of 17.5 to 35.0 kg/m2; and a total body weight \>50 kg (110 lb).
6. Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

Exclusion Criteria:

1. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
2. History of human immunodeficiency virus (HIV) infection, syphilis, hepatitis B, or hepatitis C; positive testing for HIV, syphilis, HBsAg, or HCVAb. Prior Hepatitis B vaccination is allowed.
3. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
4. Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention.
5. Previous administration with an investigational drug within 4 months or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
6. A positive urine drug test.
7. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), the BP should be repeated 2 more times and the average of the 3 BP values should be used to determine the participant's eligibility.
8. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, baseline QTc interval \>450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second- or third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the baseline uncorrected QT interval is \>450 msec, this interval should be rate-corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTc or QRS values should be used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants.
9. Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat test, if deemed necessary:

   * AST or ALT level ≥1.25 × ULN;
   * Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is≤ ULN.
10. History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
11. Blood donation (excluding plasma donations) of approximately 400 mL or more within 60 days prior to dosing.
12. History of sensitivity to heparin or heparin-induced thrombocytopenia.
13. History of substance abuse within 12 months of the screening visit.
14. Pregnant females; breastfeeding females.
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol.
16. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

Primary outcomes:
measure: Area Under the Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC24h) for Vupanorsen
timeFrame: 0 hour (predose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on day 1
measure: AUC From Time 0 to 48 Hours Post-dose (AUC48h) for Vupanorsen
timeFrame: 0 hour (predose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post dose
measure: AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for Vupanorsen
timeFrame: 0 hour (predose), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose, and on days 8, 15, 30, 60 and 90
measure: Maximum Observed Concentration (Cmax)
timeFrame: 0 hour (predose), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose, and on days 8, 15, 30, 60 and 90
measure: AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Vupanorsen
timeFrame: 0 hour (predose), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose, and on days 8, 15, 30, 60 and 90
measure: Time for Cmax (Tmax) for Vupanorsen
timeFrame: 0 hour (predose), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose, and on days 8, 15, 30, 60 and 90
measure: Terminal Elimination Half Life (t½) for Vupanorsen
timeFrame: 0 hour (predose), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose, and on days 8, 15, 30, 60 and 90
measure: Apparent Clearance (CL/F) for Vupanorsen
timeFrame: 0 hour (predose), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose, and on days 8, 15, 30, 60 and 90
measure: Apparent Volume of Distribution (Vz/F) for Vupanorsen
timeFrame: 0 hour (predose), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose, and on days 8, 15, 30, 60 and 90
Secondary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Baseline through day 90
measure: Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)
timeFrame: Baseline through day 90
measure: Number of Participants With Clinically Significant Vital Sign Values
timeFrame: Baseline through day 90
measure: Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Values
timeFrame: Baseline through day 90
measure: Percent Changes From Baseline in Angiopoietin-Like 3 (ANGPTL3)
timeFrame: Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
measure: Percent Change From Baseline in Total Cholesterol
timeFrame: Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
measure: Percent Changs From Baseline in High-density Lipoprotein Cholesterol (HDL-C)
timeFrame: Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
measure: Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
timeFrame: Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
measure: Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C)
timeFrame: Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
measure: Percent Change From Baseline in Triglyceride
timeFrame: Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
measure: Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C)
timeFrame: Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
measure: Percent Change From Baseline in Apolipoprotein A-1 (ApoA-I)
timeFrame: Day 1, Day 15, Day 60, and Day 90
measure: Percent Change From Baseline in Apolipoprotein B (ApoB) Total (Including ApoB-48, ApoB-100)
timeFrame: Day 1, Day 15, Day 60, and Day 90
measure: Percent Change From Baseline in Apolipoprotein C-III (ApoC-III)
timeFrame: Day 1, Day 15, Day 60, and Day 90
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Huashan Hospital,Fudan University
state: Shanghai
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: