A Research Study Looking at How NNC0385-0434 Tablets Work to Lower Blood Cholesterol in People With Heart Disease or a High Risk of Heart Disease

Dose Response and Safety of an Oral PCSK9i, NNC0385-0434, in Patients With Established Atherosclerotic Cardiovascular Disease (ASCVD) or ASCVD Risk on Maximally Tolerated Statin Dose and Other Lipid-lowering Therapy Requiring Further LDL-C Reduction

This study looks at how well a new medicine, NNC0385-0434, works to lower blood cholesterol levels. Participants will either get NNC0385-0434 as a tablet (a potential new medicine), or placebo as a tablet (a dummy medicine that looks like NNC0385-0434 but has no effect on the body), or evolocumab as an injection (a medicine that doctors can already prescribe).

Which treatment participants get is decided by chance. If participants get NNC0385-0434 or placebo participants will need to take 1 tablet every morning. If participants get evolocumab participants will need to take 1 injection every 2 weeks.

The study will last for about 22 weeks. About 255 people will participate in the study. Participants will have 9 visits to the clinic and 2 phone calls with the study doctor. Some people will be invited to participate in a sub-study and will have 4 extra visits (13 visits in total). Participants will have blood samples taken at all visits to the clinic (except visit 0). At 4 clinic visits, participants will have an electrocardiogram (ECG). This is a test to check your heart.

Women can only take part in the study if they are not able to become pregnant.

Study Overview

• Status: Completed
• Conditions: Atherosclerotic Cardiovascular Disease
• Intervention / Treatment: Drug: NNC0385-0434 A 15 mg; Other: Placebo I A (for NNC0385-0434 A 15 mg); Drug: NNC0385-0434 A 40 mg; Other: Placebo I A (for NNC0385-0434 A 40 mg); Drug: NNC0385-0434 A 100 mg; Other: Placebo II A (for NNC0385-0434 A 100 mg); Drug: Evolocumab 140 mg/mL, Repatha®

• Study Type: Interventional
• Enrollment (Actual): 267
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Algemeen Stedelijk Ziekenhuis - Aalst - Interventional Cardiology
  • Brugge, Belgium, 8000
    • AZ Sint-Jan - Campus Brugge
  • Genk, Belgium, 3600
    • Ziekenhuis Oost-Limburg AV - Cardiology
  • Haine-Saint-Paul, Belgium, 7100
    • Hôpital de Jolimont_Haine-Saint-Paul_0
  • Hasselt, Belgium, 3500
    • Jessa Ziekenhuis - Hasselt - Cardiology
• Germany
  • Frankfurt, Germany, 60389
    • MVZ CCB Frankfurt und Main-Taunus GbR
  • Freiburg, Germany, 79106
    • Medical Center - University of Freiburg
  • München, Germany, 80636
    • Deutsches Herzzentrum München - Klinik für Herz- und Kreislauferkrankungen
  • Villingen-Schwenningen, Germany, 78048
    • Jacob, Villingen-Schwenningen
• Greece
  • Athens, Greece, 11528
    • Alexandra General Hospital, Therapeutic Clinic
  • Athens, Greece, 11527
    • "Sotiria" Thoracic Diseases Hospital of Athens
  • Athens, Greece, 14233
    • Konstantopouleio G.H. of Athens, "Agia Olga"
  • Athens, Greece, 15123
    • "Hygeia" General Hospital of Athens
  • Chaidari, Athens, Greece, 12462
    • U.G.H of Athens "Attikon"
  • Chios, Greece, 82100
    • General Hospital of Chios "Skilitsio"
• Japan
  • Saitama-shi, Saitama, Japan, 338-0837
    • Sanai Hospital
  • Sendai-shi, Miyagi, Japan, 983-0039
    • Shinden Higashi Clinic
  • Soka-shi, Saitama, Japan, 340-0015
    • Soka Sugiura Internal Medicine Clinic
  • Tokyo, Japan, 192-0918
    • Minamino Cardiovascular Hospital
• Netherlands
  • Den Bosch, Netherlands, 5223 GZ
    • Jeroen Bosch Ziekenhuis
  • Deventer, Netherlands, 7416 SE
    • Deventer Ziekenhuis
  • Groningen, Netherlands, 9728 NT
    • Martini Ziekenhuis
  • Haarlem, Netherlands, 2035 RC
    • Spaarne Gasthuis
  • Nijmegen, Netherlands, 6532 SZ
    • Canisius-Wilhelmina Ziekenhuis
  • Sneek, Netherlands, 8601 ZR
    • D & A Research B.V.
• Poland
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne
  • Lubin, Poland, 59-301
    • Regionalny Osrodek Kardiologii
  • Swidnik, Poland, 21-040
    • Lubelskie Centrum Diagnostyczne Tomasz Blicharski
  • Warszawa, Poland, 04-073
    • Szpital Grochowski im. dr med. Rafała Masztaka Sp. z o.o.
  • Warszawa, Poland, 02-097
    • Uniwersyteckie Centrum Kliniczne WUM
  • Warszawa, Poland, 04-628
    • Narodowy Instytut Kardiologii Stefana kardynała Wyszynskiego
• United States
  • California
    • Palm Springs, California, United States, 92262
      • Desert Oasis Hlthcr Med Group
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Med Ctr Clinical Trials
    • Fort Lauderdale, Florida, United States, 33312
      • Integrative Research Associates, Inc
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Ctr For Clin Res
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Northwest Heart Clin. Res.
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Louisiana Heart Center
    • Slidell, Louisiana, United States, 70458
      • Louisiana Heart Center_Slidell
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Univ of Nebraska Medical CTR
    • Omaha, Nebraska, United States, 68105
      • VA NEB - Western IA Health Stm
  • New York
    • Albany, New York, United States, 12203
      • Albany Medical College - Endo
    • West Seneca, New York, United States, 14224
      • Southgate Medical Group, LLP
  • Texas
    • Dallas, Texas, United States, 75208
      • Thyroid, Endocrinology, and Diabetes, PA
    • Houston, Texas, United States, 77079
      • PlanIt Research, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males or females of non-childbearing potential.

• Established atherosclerotic cardiovascular disease (ASCVD) (criteria a) or ASCVD risk (criteria b):

  1. Age 40 years or older at the time of signing informed consent and history of ASCVD
  2. Age above 50 years at the time of signing informed consent and with ASCVD risk
• Serum LDL-C above or equal to 1.8 mmol/L (above or equal to 70 mg/dL) as measured by the central laboratory at screening.
• Japanese participants: Serum LDL-C above or equal to 2.6 mmol/L (above or equal to 100 mg/dL) for participants of 40 years of age or older and with a history of coronary heart disease, and serum LDL-C above or equal to 3.1 mmol/L (above or equal to 120 mg/dL) for all other Japanese participants
• Participants must be on maximally tolerated dose of statins.
• Participants not receiving statin must have documented evidence of intolerance to all doses of at least two different statins.

Exclusion Criteria:

• Treatment with PCSK9i therapy (alirocumab or evolocumab within 90 days prior to screening) or PCSK9 siRNA therapy (inclisiran within 12 months prior to screening).
• Fasting triglyceride above 4.52 mmol/L (above 400 mg/dL) as measured by the central laboratory at screening.
• Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening.
• Renal impairment with eGFR less than 30 ml/min/1.73 m2 as measured by the central laboratory at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral NNC0385-0434 15 mg once-daily (OD); 15 mg NNC0385-0434 co-formulated with 500 mg Salcaprozate sodium (SNAC) tablet once daily	Drug: NNC0385-0434 A 15 mg; 15 mg administered as one oral tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces).
Placebo Comparator: Oral placebo (NNC0385-0434 15 mg); 15 MG placebo administered as tablets (without SNAC) once daily	Other: Placebo I A (for NNC0385-0434 A 15 mg); Placebo administered as 1 tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces). placebo tablets are sized match to the active arm within dose level
Experimental: Oral NNC0385-0434 40 mg OD; 40 mg study drug co-formulated with 500 mg SNAC tablet once daily	Drug: NNC0385-0434 A 40 mg; 40 mg administered as one oral tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces).
Placebo Comparator: Oral placebo (NNC0385-0434 40 mg); placebo administered as tablets (without SNAC) once daily	Other: Placebo I A (for NNC0385-0434 A 40 mg); Placebo administered as one tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces). placebo tablets are sized match to the active arm within dose level
Experimental: Oral NNC0385-0434 100 mg; 100 mg NNC0385-0434 co-formulated with 500 mg SNAC tablet once daily (51 participants)	Drug: NNC0385-0434 A 100 mg; 100 mg administered as one oral tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces).
Placebo Comparator: Oral placebo (NNC0385-0434 100 mg); placebo administered as tablets (without SNAC) once daily	Other: Placebo II A (for NNC0385-0434 A 100 mg); Placebo administered as one tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces). placebo tablets are sized match to the active arm within dose level
Active Comparator: Subcutaneous evolocumab 140 mg Q2W; 140 mg evolocumab Subcutaneous (s.c.) injections every 2 weeks (51 participants). The s.c. evolocumab arm is open-label to limit unnecessary injections	Drug: Evolocumab 140 mg/mL, Repatha®; Every 2 weeks subcutaneous (s.c.) injection of 140 mg into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. Administered using a pre-filled SureClick® autoinjector (single-use). Dose volume: 1 mL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Low-density Lipoprotein (LDL)-Cholesterol	Percentage change in LDL-cholesterol (LDL-C) (measured in milligrams per deciliter [mg/dL]) at week 12 is presented. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period. The in-trial period is defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site.	Baseline (week 0), week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Total Cholesterol	Percentage change in total cholesterol (measured in millimoles per iliter [mmol/L]) at week 12 is presented. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	Baseline (week 0), week 12
Percentage Change in High Density Lipoprotein (HDL)-Cholesterol	Percentage change in HDL-cholesterol (measured in mg/dL) at week 12 is presented. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	Baseline (week 0), week 12
Percentage Change in Very Low Density Lipoprotein (VLDL)-Cholesterol	Percentage change in VLDL-cholesterol (measured in mmol/L) at week 12 is presented. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	Baseline (week 0), week 12
Percentage Change in Triglycerides	Percentage change in triglycerides (measured in mg/dL) at week 12 is presented. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	Baseline (week 0), week 12
Percentage Change in Total Apolipoprotein B (Apo B)	Percentage change in Apo B (measured in mg/dL) at week 12 is presented. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	Baseline (week 0), week 12
Percentage Change in Total Apolipoprotein CIII (Apo CIII)	Percentage change in Apo CIII (measured in mg/dL) at week 12 is presented. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	Baseline (week 0), week 12
Change in Total Lipoprotein(a) (Lp[a]): Ratio to Baseline	Change in total Lp(a) (measured in mg/dL) at week 12 is presented as ratio to baseline. Data is reported for the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	Baseline (week 0), week 12
Number of Treatment-emergent Adverse Events (TEAEs)	An adverse events (AE) is any untoward medical occurrence in a clinical trial participant that is temporally associated with the use of an investigational medicinal product (IMP), whether or not considered related to the IMP. All presented AEs are TEAEs. TEAEs was the number of AEs recorded during the on-treatment period. The on-treatment period is the time period where participants were considered exposed to trial product. The observation period starts at the date of first dose of trial product and ends at the first date of any of the following: The follow-up visit or the last date on randomised treatment regimen + 58 days or the end-date for the 'in-trial' observation period.	From baseline (week 0) to 138 days

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S
• Investigators: Study Director: Clinical Transparency (dept. 1452), Novo Nordisk A/S

Publications and helpful links

General Publications

• Koren MJ, Descamps O, Hata Y, Hengeveld EM, Hovingh GK, Ikonomidis I, Radu Juul Jensen MD, Langbakke IH, Martens FMAC, Sondergaard AL, Witkowski A, Koenig W. PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial. Lancet Diabetes Endocrinol. 2024 Mar;12(3):174-183. doi: 10.1016/S2213-8587(23)00325-X. Epub 2024 Feb 1.

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2021
• Primary Completion (Actual): April 26, 2022
• Study Completion (Actual): June 20, 2022

Study Registration Dates

• First Submitted: July 28, 2021
• First Submitted That Met QC Criteria: July 28, 2021
• First Posted (Actual): August 5, 2021

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: June 5, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Atherosclerosis; PCSK9 Inhibitors; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Antimetabolites; Serine Proteinase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: NN6435-4697; U1111-1252-3392 (Other Identifier: World Health Organization (WHO)); 2020-002630-32 (EudraCT Number); 151409 (Other Identifier: IND Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No