A Dose-Ranging Study With Vupanorsen (TRANSLATE-TIMI 70)

Dyslipidemias Clinical Trial

Official title:

A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Dose-Ranging Study to Assess the Efficacy, Safety, and Tolerability of Vupanorsen (PF-07285557) in Statin-Treated Participants With Dyslipidemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04516291
• Other study ID #: C4491011
• Secondary ID: 2020-002796-35
• Status: Completed
• Phase: Phase 2
• Start date: September 28, 2020
• Est. completion date: December 6, 2021

Study information

• Verified date: September 2022
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, Phase 2b, double-blind, placebo-controlled, parallel group study to provide data on efficacy, safety, tolerability, and pharmacokinetics (PK) of PF-07285557 (hereafter, vupanorsen) administered subcutaneously (SC) at various doses and regimens in participants with dyslipidemia, defined in this study as participants with elevated non-HDL-C and TG who are receiving a stable dose of a statin. This study is also known as TaRgeting ANGPTL3 with an aNtiSense oLigonucleotide in AdulTs with dyslipidEmia (TRANSLATE-TIMI 70).

Description:

This study is intended to enable selection of a dose(s) for future development of vupanorsen for cardiovascular (CV) risk reduction and hypertriglyceridemia.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 286
• Est. completion date: December 6, 2021
• Est. primary completion date: September 29, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

1. Male or female participants aged =40 years at Screening.

2. Fasting non-HDL-C at Screening =100 mg/dL.

3. Fasting TG at Screening of 150 to 500 mg/dL, inclusive, which may be repeated once if deemed necessary.

4. Participants must be on a stable dose of a statin for at least 1 month before Screening and plan to remain on the same medication and dose for the duration of the study.

5. Body weight =50 kg and =136 kg at Screening.

6. Capable of giving signed informed consent.

Exclusion Criteria:

1. Participant has active liver disease (other than NAFLD or NASH, which are permitted), including chronic active hepatitis B or C or primary biliary cirrhosis.

2. Uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg). Note: participants who are on an anti-hypertensive medication to treat hypertension should be on a stable dose at least 1 month prior to Screening. The investigator should ensure participant took anti-hypertensive medication as prescribed prior to evaluation of blood pressure.

3. Participant with a known bleeding diathesis or coagulation disorder.

4. Participants with ANY of the following abnormalities in clinical laboratory tests at Screening, as assessed by the central laboratory and confirmed by a single repeat test, if deemed necessary: HbA1c =9.5% eGFR <30 mL/min/1.73 m2 (as determined by the CKD-Epi equation) ALT or AST >2 × ULN Total bilirubin =1.5 × ULN; participants with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is =ULN Platelet count <LLN

5. History of clinically significant acute cardiac event within 3 months before Screening (includes ischemic stroke, transient ischemic attack, myocardial infarction, revascularization procedures, hospitalization for heart failure).

6. Presence of New York Heart Association Functional Classification IV heart failure symptoms at Screening.

7. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.

8. Current history of alcoholism or drug addiction according to Diagnostic and Statistical Manual of Mental Disorders IV criteria within 12 months prior to Screening. Use of any recreational drugs within 12 months prior to Screening.

9. 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.

Prior/Concomitant Therapy:

10. Prior treatment at any time with vupanorsen.

11. Prior treatment with any oligonucleotide (including small interfering ribonucleic acid) within 6 months of Screening or prior treatment with inclisiran within 12 months of Screening.

12. Use of TG lowering medication (eg, Vascepa [icosapent ethyl]), non-prescription dietary supplements (eg, fish oil) or other cholesterol lowering medication (eg, fibric acid derivatives, niacin, PCSK9 inhibitors, bile acid sequestrants, bempedoic acid) 30 days prior to Screening, other than statins and ezetimibe.

13. Use of warfarin or other coumarins, direct thrombin inhibitors, Factor Xa inhibitors, heparins or heparinoids 30 days prior to Screening.

Prior/Concurrent Clinical Study Experience:

14. Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).

Diagnostic Assessments:

15. Participant has a clinically significant ECG abnormality during the Screening Period that requires further diagnostic evaluation or intervention (eg, new, clinically significant arrhythmia or a conduction disturbance). Other Exclusions

16. Unstable weight (>5% shift in past month) or plan to start a diet for the purpose of significant weight loss.

17. Hypersensitivity to the active substance or to any of the excipients or GalNAc.

18. Any major surgery, including bariatric surgery, within 3 months of Screening.

19. Participants with conditions contraindicated for MRI procedures including pacemakers or aneurysm clips; the presence of MRI incompatible implanted devices; metallic foreign bodies; metal tattoos (including permanent make-up); or severe claustrophobia impacting the ability to perform MRI. Participants who may require mild sedative or anxiolytic in order to complete the MRI may be enrolled.

20. Participants unwilling or unable to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator.

21. 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.

Related Conditions & MeSH terms

• Dyslipidemias
• Hyperlipidemias
• Hyperlipoproteinemias

Intervention

Drug:
• Vupanorsen
Vupanorsen and placebo will be provided as prefilled syringes packaged and dispensed in cartons with tamper-evident seals. Only single-use syringes will be used.
• Placebo
Vupanorsen and placebo will be provided as prefilled syringes packaged and dispensed in cartons with tamper-evident seals. Only single-use syringes will be used.

Locations

Country	Name	City	State
Canada	LMC Clinical Research Inc. (Barrie)	Barrie	Ontario
Canada	Aggarwal and Associates Limited	Brampton	Ontario
Canada	Ecogene-21	Chicoutimi	Quebec
Canada	Resonance Magnetique du Saguenay-Lac-Saint-Jean	Chicoutimi	Quebec
Canada	LMC Clinical Research Inc. (Thornhill)	Concord	Ontario
Canada	C-endo	Edmonton	Alberta
Canada	MIC Medical Imaging	Edmonton	Alberta
Canada	LMC Clinical Research Inc. (Etobicoke)	Etobicoke	Ontario
Canada	Dawson Clinical Research	Guelph	Ontario
Canada	Nova Scotia Health Authority QE II Health Sciences Centre	Halifax	Nova Scotia
Canada	Nova Scotia Health Authority QE II Health Sciences Centre	Halifax	Nova Scotia
Canada	KMH Cardiology Centres Inc.	Kitchener	Ontario
Canada	Milestone Research Inc.	London	Ontario
Canada	Robarts Research Institute, Western University	London	Ontario
Canada	Manna Research (Mirabel)	Mirabel	Quebec
Canada	GNMI Medical Imaging	Mississauga	Ontario
Canada	GNMI Medical Imaging	Mississauga	Ontario
Canada	GNMI MRI and CT Medical Imaging	Mississauga	Ontario
Canada	Montreal Heart Institute	Montreal	Quebec
Canada	Recherche GCP Research	Montreal	Quebec
Canada	Research Institute of the McGill University Health Center	Montreal	Quebec
Canada	Research Institute of the McGill University Health Centre	Montreal	Quebec
Canada	North York Diagnostic and Cardiac Centre	North York	Ontario
Canada	Radimed West Island	Pointe-Claire	Quebec
Canada	Alpha Recherche Clinique	Quebec
Canada	Centre de Recherche Saint-Louis	Quebec
Canada	Diex Recherche Quebec Inc.	Quebec
Canada	IRM Quebec - Complexe Synase	Quebec
Canada	IRM Quebec Synase	Quebec
Canada	Bluewater Clinical Research Group Inc.	Sarnia	Ontario
Canada	Synergy Medical Clinic	Sherwood Park	Alberta
Canada	Diex Recherche Joliette	St-Charles-Borromee	Quebec
Canada	Access MRI	Surrey	British Columbia
Canada	SMH Cardiology Clinical Trials Inc.	Surrey	British Columbia
Canada	Dr. Anil K. Gupta Medicine Professional Corporation	Toronto	Ontario
Canada	Holland Bloorview Kids Rehabilitation Hospital	Toronto	Ontario
Canada	Devonshire Clinical Research Inc.	Woodstock	Ontario
Poland	ClinicMed Daniluk, Nowak Spolka Jawna	Bialystok
Poland	NZOZ Kendron	Bialystok
Poland	Malopolskie Centrum Sercowo-Naczyniowe PAKS - Chrzanow	Chrzanow
Poland	Centrum Badan Klinicznych PI-House sp. z o.o.	Gdansk
Poland	Centrum Medyczne Enel-Med., Oddzial Alfa Plaza - Gdynia	Gdynia
Poland	HELIMED Katowice - Rezonans Magnetyczny, Tomografia Komputerowa	Katowice
Poland	HELIMED Katowice - Rezonans Magnetyczny, Tomografia Komputerowa (MRI)	Katowice
Poland	Kardio Brynow	Katowice
Poland	Niepubliczny Zaklad Opieki Zdrowotnej "TERAPIA OPTIMA"	Katowice
Poland	"TWOJA PRZYCHODNIA" Sp. z o.o.	Lublin
Poland	Top Medical Lublin	Lublin
Poland	Centrum Zdrowia Metabolicznego Pawel Bogdanski	Poznan
Poland	Arterieart Sp. z o.o.	Puszczykowo
Poland	SZPITAL SW. ELZBIETY W KATOWICACH Polsko-Amerykanskie Kliniki Serca	Tychy
Poland	Futuremeds	Wroclaw
Poland	Skanmex (MRI)	Wroclaw
Poland	TOMMA Pracownia rezonansu magnetycznego we Wroclawiu	Wroclaw
Poland	Wro Medica	Wroclaw
United States	Capital Cardiology Associates	Albany	New York
United States	Randolph Health Internal Medicine	Asheboro	North Carolina
United States	Randolph Health MRI Center	Asheboro	North Carolina
United States	Maryland Cardiovascular Specialists	Baltimore	Maryland
United States	Seton Imaging Center	Baltimore	Maryland
United States	Tower Radiology	Brandon	Florida
United States	Tower Radiology Parsons	Brandon	Florida
United States	Lahey Clinic Hospital and Medical Center	Burlington	Massachusetts
United States	PMG Research of Raleigh, LLC d/b/a PMG Research of Cary	Cary	North Carolina
United States	Wake Radiology	Cary	North Carolina
United States	Hightop Medical Research Center	Cincinnati	Ohio
United States	Imaging Research Center-Cincinnati Children's	Cincinnati	Ohio
United States	Innovative Research of West Florida, Inc.	Clearwater	Florida
United States	Dallas Diabetes Research Center	Dallas	Texas
United States	Southwest Diagnostic Imaging Center	Dallas	Texas
United States	Alliance for Multispecialty Research, LLC	El Dorado	Kansas
United States	Susan B. Allen Memorial Hospital	El Dorado	Kansas
United States	Horizon Clinical Research Associates, PLLC	Gilbert	Arizona
United States	Scottsdale Medical Imaging Research, LLC	Gilbert	Arizona
United States	Pentucket Medical Associates	Haverhill	Massachusetts
United States	Pueblo Medical Imaging	Henderson	Nevada
United States	Viable Research Management LLC	Henderson	Nevada
United States	SimonMed Houston	Houston	Texas
United States	Southwest Clinical Trials	Houston	Texas
United States	Borland-Groover Clinic	Jacksonville	Florida
United States	Care Partners Clinical Research, LLC	Jacksonville	Florida
United States	Precision Imaging Centers	Jacksonville	Florida
United States	Westside Center for Clinical Research	Jacksonville	Florida
United States	ImageCare Latham	Latham	New York
United States	Clinical Trials Research	Lincoln	California
United States	Atria Clinical Research	Little Rock	Arkansas
United States	CARTI	Little Rock	Arkansas
United States	Heartland Imaging	Louisville	Kentucky
United States	L-MARC Research Center	Louisville	Kentucky
United States	Advanced Research Institute, Inc.	New Port Richey	Florida
United States	Medical Center Hospital	Odessa	Texas
United States	Permian Research Foundation	Odessa	Texas
United States	Clermont Radiology Orangeburg	Orangeburg	South Carolina
United States	South Carolina Clinical Research LLC	Orangeburg	South Carolina
United States	Sand Lakes Imaging	Orlando	Florida
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Perelman Center for Advanced Medicine, Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Accellacare - Raleigh	Raleigh	North Carolina
United States	PMG Research of Raleigh, LLC	Raleigh	North Carolina
United States	Wake Radiology Diagnostic Imaging Inc	Raleigh	North Carolina
United States	Rainier Clinical Research Center	Renton	Washington
United States	National Clinical Research, Inc.	Richmond	Virginia
United States	Diagnostic Radiological Imaging	Sacramento	California
United States	St Johns Center for Clinical Research	Saint Augustine	Florida
United States	Regions Hospital - HealthPartners	Saint Paul	Minnesota
United States	J. Lewis Research, Inc. / Foothill Family Clinic South	Salt Lake City	Utah
United States	West Coast Radiology	Santa Ana	California
United States	Bellevue Medical Imaging	Seattle	Washington
United States	Universal Research Group, LLC	Tacoma	Washington
United States	Tennessee Center for Clinical Trials	Tullahoma	Tennessee
United States	Tullahoma HMA, LLC d\b\a Tennova HealthCare Harton	Tullahoma	Tennessee
United States	University Clinical Investigators, Inc.	Tustin	California
United States	PMG Research of Winston-Salem, LLC	Winston-Salem	North Carolina
United States	Clinical Research of Central Florida	Winter Haven	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	TIMI Study Group

Countries where clinical trial is conducted

United States,  Canada,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24	Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.	Baseline, Week 24
Secondary	Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16	Blood samples were collected from participants in a fasted state for the measurement of TG, ApoB, HDL-C and LDL-C. Fasting was required at least 10 hours before blood sample collection. Non-HDL-C was calculated as total cholesterol minus HDL cholesterol. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.	Baseline, Week 16
Secondary	Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24	Fasting was required for all lipid measures at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.	Baseline, Week 24
Secondary	Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16	ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the angiopoietin-like family of proteins. Blood samples were collected from participants in a fasted state for the measurement of ANGPTL3. Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.	Baseline, Week 16
Secondary	Percent Change From Baseline in ANGPTL3 at Week 24	ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the angiopoietin-like family of proteins. Blood samples were collected from participants in a fasted state for the measurement of ANGPTL3. Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.	Baseline, Week 24

External Links

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