Clinical trial NCT04516291: A Dose-Ranging Study With Vupanorsen (TRANSLATE-TIMI 70)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Dyslipidemias
Hyperlipidemias
Hyperlipoproteinemias
Keywords: Primary hyperlipidemia
Mixed dyslipidemia
Lipid Metabolism Disorders
Metabolic Diseases
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: The TIMI Study Group
First posted: 2020-08-18
Enrollment: 286
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

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

Eligibility criteria: 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.

Primary outcomes:
measure: Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline in ANGPTL3 at Week 24
timeFrame: Baseline, Week 24
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Horizon Clinical Research Associates, PLLC
state: Arizona
city: Gilbert
country: United States
facility: Scottsdale Medical Imaging Research, LLC
state: Arizona
city: Little Rock
country: United States
facility: CARTI
state: Arkansas
city: Little Rock
country: United States
facility: Atria Clinical Research
state: Arkansas
city: Lincoln
country: United States
facility: Clinical Trials Research
state: California
city: Sacramento
country: United States
facility: Diagnostic Radiological Imaging
state: California
city: Santa Ana
country: United States
facility: West Coast Radiology
state: California
city: Tustin
country: United States
facility: University Clinical Investigators, Inc.
state: California
city: Brandon
country: United States
facility: Tower Radiology Parsons
state: Florida
city: Brandon
country: United States
facility: Tower Radiology
state: Florida
city: Clearwater
country: United States
facility: Innovative Research of West Florida, Inc.
state: Florida
city: Jacksonville
country: United States
facility: Westside Center for Clinical Research
state: Florida
city: Jacksonville
country: United States
facility: Borland-Groover Clinic
state: Florida
city: Jacksonville
country: United States
facility: Precision Imaging Centers
state: Florida
city: Jacksonville
country: United States
facility: Care Partners Clinical Research, LLC
state: Florida
city: New Port Richey
country: United States
facility: Advanced Research Institute, Inc.
state: Florida
city: Orlando
country: United States
facility: Sand Lakes Imaging
state: Florida
city: Saint Augustine
country: United States
facility: St Johns Center for Clinical Research
state: Florida
city: Winter Haven
country: United States
facility: Clinical Research of Central Florida
state: Florida
city: El Dorado
country: United States
facility: Alliance for Multispecialty Research, LLC
state: Kansas
city: El Dorado
country: United States
facility: Susan B. Allen Memorial Hospital
state: Kansas
city: Louisville
country: United States
facility: L-MARC Research Center
state: Kentucky
city: Louisville
country: United States
facility: Heartland Imaging
state: Kentucky
city: Baltimore
country: United States
facility: Maryland Cardiovascular Specialists
state: Maryland
city: Baltimore
country: United States
facility: Seton Imaging Center
state: Maryland
city: Burlington
country: United States
facility: Lahey Clinic Hospital and Medical Center
state: Massachusetts
city: Haverhill
country: United States
facility: Pentucket Medical Associates
state: Massachusetts
city: Saint Paul
country: United States
facility: Regions Hospital - HealthPartners
state: Minnesota
city: Henderson
country: United States
facility: Viable Research Management LLC
state: Nevada
city: Henderson
country: United States
facility: Pueblo Medical Imaging
state: Nevada
city: Albany
country: United States
facility: Capital Cardiology Associates
state: New York
city: Latham
country: United States
facility: ImageCare Latham
state: New York
city: Asheboro
country: United States
facility: Randolph Health Internal Medicine
state: North Carolina
city: Asheboro
country: United States
facility: Randolph Health MRI Center
state: North Carolina
city: Cary
country: United States
facility: PMG Research of Raleigh, LLC d/b/a PMG Research of Cary
state: North Carolina
city: Cary
country: United States
facility: Wake Radiology
state: North Carolina
city: Raleigh
country: United States
facility: Accellacare - Raleigh
state: North Carolina
city: Raleigh
country: United States
facility: PMG Research of Raleigh, LLC
state: North Carolina
city: Raleigh
country: United States
facility: Wake Radiology Diagnostic Imaging Inc
state: North Carolina
city: Winston-Salem
country: United States
facility: PMG Research of Winston-Salem, LLC
state: North Carolina
city: Cincinnati
country: United States
facility: Hightop Medical Research Center
state: Ohio
city: Cincinnati
country: United States
facility: Imaging Research Center-Cincinnati Children's
state: Ohio
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Perelman Center for Advanced Medicine, Hospital of the University of Pennsylvania
state: Pennsylvania
city: Orangeburg
country: United States
facility: Clermont Radiology Orangeburg
state: South Carolina
city: Orangeburg
country: United States
facility: South Carolina Clinical Research LLC
state: South Carolina
city: Tullahoma
country: United States
facility: Tennessee Center for Clinical Trials
state: Tennessee
city: Tullahoma
country: United States
facility: Tullahoma HMA, LLC d\b\a Tennova HealthCare Harton
state: Tennessee
city: Dallas
country: United States
facility: Dallas Diabetes Research Center
state: Texas
city: Dallas
country: United States
facility: Southwest Diagnostic Imaging Center
state: Texas
city: Houston
country: United States
facility: SimonMed Houston
state: Texas
city: Houston
country: United States
facility: Southwest Clinical Trials
state: Texas
city: Odessa
country: United States
facility: Medical Center Hospital
state: Texas
city: Odessa
country: United States
facility: Permian Research Foundation
state: Texas
city: Salt Lake City
country: United States
facility: J. Lewis Research, Inc. / Foothill Family Clinic South
state: Utah
city: Richmond
country: United States
facility: National Clinical Research, Inc.
state: Virginia
city: Renton
country: United States
facility: Rainier Clinical Research Center
state: Washington
city: Seattle
country: United States
facility: Bellevue Medical Imaging
state: Washington
city: Tacoma
country: United States
facility: Universal Research Group, LLC
state: Washington
city: Edmonton
country: Canada
facility: C-endo
state: Alberta
city: Edmonton
country: Canada
facility: MIC Medical Imaging
state: Alberta
city: Sherwood Park
country: Canada
facility: Synergy Medical Clinic
state: Alberta
city: Surrey
country: Canada
facility: Access MRI
state: British Columbia
city: Surrey
country: Canada
facility: SMH Cardiology Clinical Trials Inc.
state: British Columbia
city: Halifax
country: Canada
facility: Nova Scotia Health Authority QE II Health Sciences Centre
state: Nova Scotia
city: Halifax
country: Canada
facility: Nova Scotia Health Authority QE II Health Sciences Centre
state: Nova Scotia
city: Barrie
country: Canada
facility: LMC Clinical Research Inc. (Barrie)
state: Ontario
city: Brampton
country: Canada
facility: Aggarwal and Associates Limited
state: Ontario
city: Concord
country: Canada
facility: LMC Clinical Research Inc. (Thornhill)
state: Ontario
city: Etobicoke
country: Canada
facility: LMC Clinical Research Inc. (Etobicoke)
state: Ontario
city: Guelph
country: Canada
facility: Dawson Clinical Research
state: Ontario
city: Kitchener
country: Canada
facility: KMH Cardiology Centres Inc.
state: Ontario
city: London
country: Canada
facility: Milestone Research Inc.
state: Ontario
city: London
country: Canada
facility: Robarts Research Institute, Western University
state: Ontario
city: Mississauga
country: Canada
facility: GNMI Medical Imaging
state: Ontario
city: Mississauga
country: Canada
facility: GNMI Medical Imaging
state: Ontario
city: Mississauga
country: Canada
facility: GNMI MRI and CT Medical Imaging
state: Ontario
city: North York
country: Canada
facility: North York Diagnostic and Cardiac Centre
state: Ontario
city: Sarnia
country: Canada
facility: Bluewater Clinical Research Group Inc.
state: Ontario
city: Toronto
country: Canada
facility: Holland Bloorview Kids Rehabilitation Hospital
state: Ontario
city: Toronto
country: Canada
facility: Dr. Anil K. Gupta Medicine Professional Corporation
state: Ontario
city: Woodstock
country: Canada
facility: Devonshire Clinical Research Inc.
state: Ontario
city: Chicoutimi
country: Canada
facility: Resonance Magnetique du Saguenay-Lac-Saint-Jean
state: Quebec
city: Chicoutimi
country: Canada
facility: Ecogene-21
state: Quebec
city: Mirabel
country: Canada
facility: Manna Research (Mirabel)
state: Quebec
city: Montreal
country: Canada
facility: Recherche GCP Research
state: Quebec
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Montreal
country: Canada
facility: Research Institute of the McGill University Health Center
state: Quebec
city: Montreal
country: Canada
facility: Research Institute of the McGill University Health Centre
state: Quebec
city: Pointe-Claire
country: Canada
facility: Radimed West Island
state: Quebec
city: St-Charles-Borromee
country: Canada
facility: Diex Recherche Joliette
state: Quebec
city: Quebec
country: Canada
facility: IRM Quebec - Complexe Synase
city: Quebec
country: Canada
facility: IRM Quebec Synase
city: Quebec
country: Canada
facility: Diex Recherche Quebec Inc.
city: Quebec
country: Canada
facility: Centre de Recherche Saint-Louis
city: Quebec
country: Canada
facility: Alpha Recherche Clinique
city: Bialystok
country: Poland
facility: NZOZ Kendron
city: Bialystok
country: Poland
facility: ClinicMed Daniluk, Nowak Spolka Jawna
city: Chrzanow
country: Poland
facility: Malopolskie Centrum Sercowo-Naczyniowe PAKS - Chrzanow
city: Gdansk
country: Poland
facility: Centrum Badan Klinicznych PI-House sp. z o.o.
city: Gdynia
country: Poland
facility: Centrum Medyczne Enel-Med., Oddzial Alfa Plaza - Gdynia
city: Katowice
country: Poland
facility: Kardio Brynow
city: Katowice
country: Poland
facility: Niepubliczny Zaklad Opieki Zdrowotnej "TERAPIA OPTIMA"
city: Katowice
country: Poland
facility: HELIMED Katowice - Rezonans Magnetyczny, Tomografia Komputerowa (MRI)
city: Katowice
country: Poland
facility: HELIMED Katowice - Rezonans Magnetyczny, Tomografia Komputerowa
city: Lublin
country: Poland
facility: "TWOJA PRZYCHODNIA" Sp. z o.o.
city: Lublin
country: Poland
facility: Top Medical Lublin
city: Poznan
country: Poland
facility: Centrum Zdrowia Metabolicznego Pawel Bogdanski
city: Puszczykowo
country: Poland
facility: Arterieart Sp. z o.o.
city: Tychy
country: Poland
facility: SZPITAL SW. ELZBIETY W KATOWICACH Polsko-Amerykanskie Kliniki Serca
city: Wroclaw
country: Poland
facility: Futuremeds
city: Wroclaw
country: Poland
facility: Skanmex (MRI)
city: Wroclaw
country: Poland
facility: Wro Medica
city: Wroclaw
country: Poland
facility: TOMMA Pracownia rezonansu magnetycznego we Wroclawiu
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Bergmark BA, Marston NA, Bramson CR, Curto M, Ramos V, Jevne A, Kuder JF, Park JG, Murphy SA, Verma S, Wojakowski W, Terra SG, Sabatine MS, Wiviott SD; TRANSLATE-TIMI 70 Investigators. Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70. Circulation. 2022 May 3;145(18):1377-1386. doi: 10.1161/CIRCULATIONAHA.122.059266. Epub 2022 Apr 3.