A Study To Investigate The Pharmacokinetics, Pharmacodynamics, Safety And Tolerability Of Single Dose Vupanorsen In Healthy Chinese Adults

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Vupanorsen

• Registration Number: NCT04916795
• Lead Sponsor: Pfizer

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2021-06-01
• Study First Submitted QC: 2021-06-01
• Study First Posted: 2021-06-08
• Study Start: 2021-06-17
• Primary Completion: 2021-10-19
• Study Completion: 2021-10-19
• Results First Submitted: 2022-09-02
• Status Verified: 2023-08
• Results First Submitted QC: 2023-08-20
• Last Update Submitted: 2023-08-20
• Results First Posted: 2024-03-12
• Last Update Posted: 2024-03-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vupanorsen 80 milligram (mg)	Vupanorsen	Participants will receive one, 0.8 milliliter (mL) subcutaneous injection with vupanorsen 100 mg/mL solution
Vupanorsen 160 milligram (mg)	Vupanorsen	Participants will receive two, 0.8 mL subcutaneous injections with vupanorsen 100 mg/mL solution

Primary Outcome Measures

Name	Time	Method
Area Under the Curve (AUC) From Time 0 to 24 Hours Post-dose (AUC24h) for Vupanorsen	0 hour (predose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post dose on day 1	AUC24h is the area under the concentration-time profile from time 0 to 24 hour post-dose
Maximum Observed Concentration (Cmax)	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	Maximum plasma concentration observed from data
AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Vupanorsen	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	AUCinf is area under the plasma concentration-time profile from time zero extrapolated to infinite time
AUC From Time 0 to 48 Hours Post-dose (AUC48h) for Vupanorsen	0 hour (predose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post dose	AUC48h is the area under the plasma concentration-time profile from time zero to the quantifiable concentration 48 hours post-dose
AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) for Vupanorsen	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	AUClast is the area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (Clast)
Terminal Elimination Half Life (t½) for Vupanorsen	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	terminal elimination half life (t½) for vupanorsen
Time for Cmax (Tmax) for Vupanorsen	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	Time for Cmax (Tmax) for vupanorsen
Apparent Clearance (CL/F) for Vupanorsen	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	Apparent clearance for vupanorsen
Apparent Volume of Distribution (Vz/F) for Vupanorsen	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	Apparent volume of distribution for vupanorsen

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Clinically Significant Vital Sign Values	Baseline through day 90	Vital sign data included blood pressure and pulse rate. Clinical significance was assessed by the investigator.
Percent Changes From Baseline in Angiopoietin-Like 3 (ANGPTL3)	Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90	Percent changes from baseline in ANGPTL3 on Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Baseline through day 90	Adverse events (AEs): any untoward medical occurrence in a clinical investigation participant administered a product or medical device, without regard to causality. Treatment-emergent AEs (TEAEs): AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. AEs included SAEs and non-serious AEs. Treatment-related TEAEs were any untoward medical occurrence attributed to study treatment. Causality to study treatment was determined by the investigator.
Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)	Baseline through day 90	Protocol-required safety laboratory assessments included chemistry, hematology, and urinalysis (and microscopy, if needed). Each parameter was evaluated against commonly used and widely accepted criteria.
Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Values	Baseline through day 90	Clinical significance of ECG data was assessed by the investigator.
Percent Change From Baseline in Triglyceride	Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90	Percentage changes from baseline in triglyceride on Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
Percent Change From Baseline in Apolipoprotein A-1 (ApoA-I)	Day 1, Day 15, Day 60, and Day 90	Percentage changes from baseline in ApoA-I on Day 15, Day 60, and Day 90. This endpoint was terminated due to changes of development plan.
Percent Change From Baseline in Apolipoprotein C-III (ApoC-III)	Day 1, Day 15, Day 60, and Day 90	Percentage changes from baseline in apolipoprotein C-III (ApoC-III) on Day 15, Day 60, and Day 90. This endpoint was terminated due to changes of development plan.
Percent Change From Baseline in Total Cholesterol	Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90	Percentage changes from baseline in total cholesterol on Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90	Percentage changes from baseline in LDL-C on Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
Percent Changs From Baseline in High-density Lipoprotein Cholesterol (HDL-C)	Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90	Percentage changes from baseline in HDL-C on Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C)	Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90	Percentage changes from baseline in VLDL-C on Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C)	Day 1, Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90	Percentage changes from baseline in non-HDL on Day 2, Day 3, Day 8, Day 15, Day 30, Day 60 and Day 90
Percent Change From Baseline in Apolipoprotein B (ApoB) Total (Including ApoB-48, ApoB-100)	Day 1, Day 15, Day 60, and Day 90	Percentage changes from baseline in ApoB total (including ApoB-48, ApoB-100) on Day 15, Day 60, and Day 90. This endpoint was terminated due to changes of development plan.

Trial Locations

Locations (1)

Huashan Hospital,Fudan University; 🇨🇳 Shanghai, Shanghai, China